U.S. patent application number 15/979932 was filed with the patent office on 2018-09-27 for 3-(carboxyethyl)-8-amino-2-oxo-1,3-diaza-spiro-[4.5]-decane derivatives.
This patent application is currently assigned to GRUENENTHAL GMBH. The applicant listed for this patent is GRUENENTHAL GMBH. Invention is credited to Florian JAKOB, Ruth JOSTOCK, Achim KLESS, Thomas KOCH, Rene Michael KOENIGS, Sven KUEHNERT, Klaus LINZ, Paul RATCLIFFE, Wolfgang SCHROEDER, Anita WEGERT.
Application Number | 20180273491 15/979932 |
Document ID | / |
Family ID | 55129632 |
Filed Date | 2018-09-27 |
United States Patent
Application |
20180273491 |
Kind Code |
A1 |
KUEHNERT; Sven ; et
al. |
September 27, 2018 |
3-(CARBOXYETHYL)-8-AMINO-2-OXO-1,3-DIAZA-SPIRO-[4.5]-DECANE
DERIVATIVES
Abstract
The invention relates to
3-(carboxyethyl)-8-amino-2-oxo-1,3-diaza-spiro-[4.5]-decane
derivatives, their preparation and their use in medicine,
particularly in the treatment of pain.
Inventors: |
KUEHNERT; Sven; (Dueren,
DE) ; KOENIGS; Rene Michael; (Erkelenz, DE) ;
JAKOB; Florian; (Aachen, DE) ; KLESS; Achim;
(Aachen, DE) ; WEGERT; Anita; (Aldenhoven, DE)
; RATCLIFFE; Paul; (Aachen, DE) ; JOSTOCK;
Ruth; (Stolberg, DE) ; KOCH; Thomas;
(Stolberg, DE) ; LINZ; Klaus; (Rheinbach, DE)
; SCHROEDER; Wolfgang; (Aachen, DE) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
GRUENENTHAL GMBH |
AACHEN |
|
DE |
|
|
Assignee: |
GRUENENTHAL GMBH
AACHEN
DE
|
Family ID: |
55129632 |
Appl. No.: |
15/979932 |
Filed: |
May 15, 2018 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
15405482 |
Jan 13, 2017 |
|
|
|
15979932 |
|
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61P 25/18 20180101;
C07D 413/12 20130101; A61P 29/00 20180101; A61P 25/30 20180101;
A61P 25/36 20180101; C07D 403/06 20130101; A61P 25/28 20180101;
A61P 25/00 20180101; A61P 43/00 20180101; C07D 405/12 20130101;
A61P 25/04 20180101; C07D 401/12 20130101; C07D 417/06 20130101;
C07D 403/12 20130101; C07D 401/06 20130101; C07D 235/02 20130101;
C07D 487/04 20130101 |
International
Class: |
C07D 235/02 20060101
C07D235/02; C07D 405/12 20060101 C07D405/12; C07D 487/04 20060101
C07D487/04; C07D 401/06 20060101 C07D401/06; C07D 403/12 20060101
C07D403/12; C07D 413/12 20060101 C07D413/12; C07D 403/06 20060101
C07D403/06; C07D 401/12 20060101 C07D401/12; C07D 417/06 20060101
C07D417/06 |
Foreign Application Data
Date |
Code |
Application Number |
Jan 13, 2016 |
EP |
16 151 011.0 |
Claims
1. A compound according to general formula (I) ##STR00202## wherein
R.sup.1 and R.sup.2 independently of one another mean --H;
--C.sub.1-C.sub.6-alkyl, linear or branched, saturated or
unsaturated, unsubstituted or substituted with one, two, three or
four substituents independently of one another selected from the
group consisting of --F, --Cl, --Br, --I, --OH, --OCH.sub.3, --CN
and --CO.sub.2CH.sub.3; a 3-12-membered cycloalkyl moiety,
saturated or unsaturated, unsubstituted or substituted with one,
two, three or four substituents independently of one another
selected from the group consisting of --F, --Cl, --Br, --I, --OH,
--OCH.sub.3, --CN and --CO.sub.2CH.sub.3; wherein said
3-12-membered cycloalkyl moiety is optionally connected through
--C.sub.1-C.sub.6-alkylene-, linear or branched, saturated or
unsaturated, unsubstituted; or a 3-12-membered heterocycloalkyl
moiety, saturated or unsaturated, unsubstituted or substituted with
one, two, three or four substituents independently of one another
selected from the group consisting of --F, --Cl, --Br, --I, --OH,
--OCH.sub.3, --CN and --CO.sub.2CH.sub.3; wherein said
3-12-membered heterocycloalkyl moiety is optionally connected
through --C.sub.1-C.sub.6-alkylene-, linear or branched, saturated
or unsaturated, unsubstituted; or R.sup.1 and R.sup.2 together with
the nitrogen atom to which they are attached form a ring and mean
--(CH.sub.2).sub.3-6--; --(CH.sub.2).sub.2--O--(CH.sub.2).sub.2--;
or --(CH.sub.2).sub.2--NR.sup.A--(CH.sub.2).sub.2--, wherein K
means --H or --C.sub.1-C.sub.6-alkyl, linear or branched, saturated
or unsaturated, unsubstituted or substituted with one, two, three
or four substituents independently of one another selected from the
group consisting of --F, --Cl, --Br and --I; R.sup.3 means
--C.sub.1-C.sub.6-alkyl, linear or branched, saturated or
unsaturated, unsubstituted, mono- or polysubstituted; a
3-12-membered cycloalkyl moiety, saturated or unsaturated,
unsubstituted, mono- or polysubstituted; wherein said 3-12-membered
cycloalkyl moiety is optionally connected through
--C.sub.1-C.sub.6-alkylene-, linear or branched, saturated or
unsaturated, unsubstituted, mono- or polysubstituted; a
3-12-membered heterocycloalkyl moiety, saturated or unsaturated,
unsubstituted, mono- or polysubstituted; wherein said 3-12-membered
heterocycloalkyl moiety is optionally connected through
--C.sub.1-C.sub.6-alkylene-, linear or branched, saturated or
unsaturated, unsubstituted, mono- or polysubstituted; a
6-14-membered aryl moiety, unsubstituted, mono- or polysubstituted;
wherein said 6-14-membered aryl moiety is optionally connected
through --C.sub.1-C.sub.6-alkylene-, linear or branched, saturated
or unsaturated, unsubstituted, mono- or polysubstituted; or a
5-14-membered heteroaryl moiety, unsubstituted, mono- or
polysubstituted; wherein said 5-14-membered heteroaryl moiety is
optionally connected through --C.sub.1-C.sub.6-alkylene-, linear or
branched, saturated or unsaturated, unsubstituted, mono- or
polysubstituted; R.sup.4 means --H; --C.sub.1-C.sub.6-alkyl, linear
or branched, saturated or unsaturated, unsubstituted, mono- or
polysubstituted; wherein said --C.sub.1-C.sub.6-alkyl is optionally
connected through --C(.dbd.O)--, --C(.dbd.O)O--, or
--S(.dbd.O).sub.2--; a 3-12-membered cycloalkyl moiety, saturated
or unsaturated, unsubstituted, mono- or polysubstituted; wherein
said 3-12-membered cycloalkyl moiety is optionally connected
through --C.sub.1-C.sub.6-alkylene-, linear or branched, saturated
or unsaturated, unsubstituted, mono- or polysubstituted; or wherein
said 3-12-membered cycloalkyl moiety is optionally connected
through --C(.dbd.O)--, --C(.dbd.O)O--, --C(.dbd.O)O--CH.sub.2--, or
--S(.dbd.O).sub.2--; a 3-12-membered heterocycloalkyl moiety,
saturated or unsaturated, unsubstituted, mono- or polysubstituted;
wherein said 3-12-membered heterocycloalkyl moiety is optionally
connected through --C.sub.1-C.sub.6-alkylene-, linear or branched,
saturated or unsaturated, unsubstituted, mono- or polysubstituted;
or wherein said 3-12-membered heterocycloalkyl moiety is optionally
connected through --C(.dbd.O)--, --C(.dbd.O)O--,
--C(.dbd.O)O--CH.sub.2--, or --S(.dbd.O).sub.2--; a 6-14-membered
aryl moiety, unsubstituted, mono- or polysubstituted; wherein said
6-14-membered aryl moiety is optionally connected through
--C.sub.1-C.sub.6-alkylene-, linear or branched, saturated or
unsaturated, unsubstituted, mono- or polysubstituted; or wherein
said 6-14-membered aryl moiety is optionally connected through
--C(.dbd.O)--, --C(.dbd.O)O--, --C(.dbd.O)O--CH.sub.2--, or
--S(.dbd.O).sub.2--; or a 5-14-membered heteroaryl moiety,
unsubstituted, mono- or polysubstituted; wherein said 5-14-membered
heteroaryl moiety is optionally connected through
--C.sub.1-C.sub.6-alkylene-, linear or branched, saturated or
unsaturated, unsubstituted, mono- or polysubstituted; or wherein
said 5-14-membered heteroaryl moiety is optionally connected
through --C(.dbd.O)--, --C(.dbd.O)O--, --C(.dbd.O)O--CH.sub.2--, or
--S(.dbd.O).sub.2--; X means --O--, --S-- or --NR.sup.6--; R.sup.5
means --H; --C.sub.1-C.sub.6-alkyl, linear or branched, saturated
or unsaturated, unsubstituted, mono- or polysubstituted; a
3-12-membered cycloalkyl moiety, saturated or unsaturated,
unsubstituted, mono- or polysubstituted; wherein said 3-12-membered
cycloalkyl moiety is optionally connected through
--C.sub.1-C.sub.6-alkylene-, linear or branched, saturated or
unsaturated, unsubstituted, mono- or polysubstituted; a
3-12-membered heterocycloalkyl moiety, saturated or unsaturated,
unsubstituted, mono- or polysubstituted; wherein said 3-12-membered
heterocycloalkyl moiety is optionally connected through
--C.sub.1-C.sub.6-alkylene-, linear or branched, saturated or
unsaturated, unsubstituted, mono- or polysubstituted; a
6-14-membered aryl moiety, unsubstituted, mono- or polysubstituted;
wherein said 6-14-membered aryl moiety is optionally connected
through --C.sub.1-C.sub.6-alkylene-, linear or branched, saturated
or unsaturated, unsubstituted, mono- or polysubstituted; or a
5-14-membered heteroaryl moiety, unsubstituted, mono- or
polysubstituted; wherein said 5-14-membered heteroaryl moiety is
optionally connected through --C.sub.1-C.sub.6-alkylene-, linear or
branched, saturated or unsaturated, unsubstituted, mono- or
polysubstituted; in case X means NR.sup.6, NR.sup.6 means --H;
--C.sub.1-C.sub.6-alkyl, linear or branched, saturated or
unsaturated, unsubstituted, mono- or polysubstituted; a
3-12-membered cycloalkyl moiety, saturated or unsaturated,
unsubstituted, mono- or polysubstituted; wherein said 3-12-membered
cycloalkyl moiety is optionally connected through
--C.sub.1-C.sub.6-alkylene-, linear or branched, saturated or
unsaturated, unsubstituted, mono- or polysubstituted; a
3-12-membered heterocycloalkyl moiety, saturated or unsaturated,
unsubstituted, mono- or polysubstituted; wherein said 3-12-membered
heterocycloalkyl moiety is optionally connected through
--C.sub.1-C.sub.6-alkylene-, linear or branched, saturated or
unsaturated, unsubstituted, mono- or polysubstituted; a
6-14-membered aryl moiety, unsubstituted, mono- or polysubstituted;
wherein said 6-14-membered aryl moiety is optionally connected
through --C.sub.1-C.sub.6-alkylene-, linear or branched, saturated
or unsaturated, unsubstituted, mono- or polysubstituted; or a
5-14-membered heteroaryl moiety, unsubstituted, mono- or
polysubstituted; wherein said 5-14-membered heteroaryl moiety is
optionally connected through --C.sub.1-C.sub.6-alkylene-, linear or
branched, saturated or unsaturated, unsubstituted, mono- or
polysubstituted; or in case X means NR.sup.6, R.sup.5 and R.sup.6
together with the nitrogen atom to which they are attached form a
3-12-membered heterocycloalkyl moiety, saturated or unsaturated,
unsubstituted, mono- or polysubstituted; R.sup.7, R.sup.8, R.sup.9,
R.sup.10, R.sup.11, R.sup.12, R.sup.13, R.sup.14, R.sup.15,
R.sup.16, R.sup.17, R.sup.18, R.sup.19, and R.sup.20 independently
of one another mean --H, --F, --Cl, --Br, --I, --OH, or
--C.sub.1-C.sub.6-alkyl, linear or branched, saturated or
unsaturated, unsubstituted, mono- or polysubstituted; or R.sup.7
and R.sup.8 together with the carbon atom to which they are
attached form a 3-12-membered cycloalkyl moiety, saturated or
unsaturated, unsubstituted, mono- or polysubstituted; or a
3-12-membered heterocycloalkyl moiety, saturated or unsaturated,
unsubstituted, mono- or polysubstituted; wherein "mono- or
polysubstituted" means that one or more hydrogen atoms are replaced
by a substituent independently of one another selected from the
group consisting of --F, --Cl, --Br, --I, --CN, --R.sup.21,
--C(.dbd.O)R.sup.21, --C(.dbd.O)OR.sup.21,
--C(.dbd.O)NR.sup.21R.sup.22,
--O--(CH.sub.2CH.sub.2--O).sub.1-30--H,
--O--(CH.sub.2CH.sub.2--O).sub.1-30--CH.sub.3, .dbd.O, --OR.sup.21,
--OC(.dbd.O)R.sup.21, --OC(.dbd.O)OR.sup.21,
--OC(.dbd.O)NR.sup.21R.sup.22, --NO.sub.2, --NR.sup.21R.sup.22,
--NR.sup.21--(CH.sub.2).sub.1-6--C(.dbd.O)R.sup.22,
--NR.sup.21--(CH.sub.2).sub.1-6--C(.dbd.O)OR.sup.22,
--NR.sup.23--(CH.sub.2).sub.1-6--C(.dbd.O)NR.sup.21R.sup.22,
NR.sup.21C(.dbd.O)R.sup.22, --NR.sup.21C(.dbd.O)--OR.sup.22,
--NR.sup.23C(.dbd.O)NR.sup.21R.sup.22,
--NR.sup.21S(.dbd.O).sub.2R.sup.22, --SR.sup.21,
--S(.dbd.O)R.sup.21, --S(.dbd.O).sub.2R.sup.21,
--S(.dbd.O).sub.2OR.sup.21, and --S(.dbd.O).sub.2NR.sup.21R.sup.22;
wherein R.sup.21, R.sup.22 and R.sup.23 independently of one
another mean --H; --C.sub.1-C.sub.6-alkyl, linear or branched,
saturated or unsaturated, unsubstituted or substituted with one,
two, three or four substituents independently of one another
selected from the group consisting of --F, --Cl, --Br, --I, --CN,
--OH, --NH.sub.2, and --O--C.sub.1-C.sub.6-alkyl; a 3-12-membered
cycloalkyl moiety, saturated or unsaturated, unsubstituted; wherein
said 3-12-membered cycloalkyl moiety is optionally connected
through --C.sub.1-C.sub.6-alkylene-, linear or branched, saturated
or unsaturated, unsubstituted or substituted with one, two, three
or four substituents independently of one another selected from the
group consisting of --F, --Cl, --Br, --I, --CN, --OH, --NH.sub.2,
--C.sub.1-C.sub.6-alkyl and --O--C.sub.1-C.sub.6-alkyl; a
3-12-membered heterocycloalkyl moiety, saturated or unsaturated,
unsubstituted; wherein said 3-12-membered heterocycloalkyl moiety
is optionally connected through --C.sub.1-C.sub.6-alkylene-, linear
or branched, saturated or unsaturated, unsubstituted or substituted
with one, two, three or four substituents independently of one
another selected from the group consisting of --F, --Cl, --Br, --I,
--CN, --OH, --NH.sub.2, --C.sub.1-C.sub.6-alkyl and
--O--C.sub.1-C.sub.6-alkyl; a 6-14-membered aryl moiety,
unsubstituted, mono- or polysubstituted; wherein said 6-14-membered
aryl moiety is optionally connected through
--C.sub.1-C.sub.6-alkylene-, linear or branched, saturated or
unsaturated, unsubstituted or substituted with one, two, three or
four substituents independently of one another selected from the
group consisting of --F, --Cl, --Br, --I, --CN, --OH, --NH.sub.2,
--C.sub.1-C.sub.6-alkyl and --O--C.sub.1-C.sub.6-alkyl; a
5-14-membered heteroaryl moiety, unsubstituted, mono- or
polysubstituted; wherein said 5-14-membered heteroaryl moiety is
optionally connected through --C.sub.1-C.sub.6-alkylene-, linear or
branched, saturated or unsaturated, unsubstituted or substituted
with one, two, three or four substituents independently of one
another selected from the group consisting of --F, --Cl, --Br, --I,
--CN, --OH, --NH.sub.2, --C.sub.1-C.sub.6-alkyl and
--O--C.sub.1-C.sub.6-alkyl; or R.sup.21 and R.sup.22 within
--C(.dbd.O)NR.sup.21R.sup.22, --OC(.dbd.O)NR.sup.21R.sup.22,
--NR.sup.21R.sup.22,
--NR.sup.23--(CH.sub.2).sub.1-6--C(.dbd.O)NR.sup.21R.sup.22,
--NR.sup.23C(.dbd.O)NR.sup.21R.sup.22, or
--S(.dbd.O).sub.2NR.sup.21R.sup.22 together with the nitrogen atom
to which they are attached form a ring and mean
--(CH.sub.2).sub.3-6--; --(CH.sub.2).sub.2--O--(CH.sub.2).sub.2--;
or --(CH.sub.2).sub.2--NR.sup.B--(CH.sub.2).sub.2--, wherein
R.sup.B means --H or --C.sub.1-C.sub.6-alkyl, linear or branched,
saturated or unsaturated, unsubstituted or substituted with one,
two, three or four substituents independently of one another
selected from the group consisting of --F, --Cl, --Br and --I; or a
physiologically acceptable salt thereof.
2. The compound according to claim 1, wherein R.sup.7 and R.sup.8
independently of one another mean --H or C.sub.1-C.sub.6-alkyl.
3. The compound according to claim 1, wherein R.sup.7 and R.sup.8
together with the carbon atom to which they are attached form a
ring selected from the group consisting of cyclopropyl, cyclobutyl
or cyclopentyl, oxetanly, tetrahydrofuranyl or tetrahydropyranyl,
in each case unsubstituted.
4. The compound according to claim 1, wherein R.sup.9, R.sup.10,
R.sup.11, R.sup.12, R.sup.13, R.sup.14, R.sup.15, R.sup.16,
R.sup.17, R.sup.18, R.sup.19, and R.sup.20 independently of one
another mean --H, --F, --OH, or --C.sub.1-C.sub.6-alkyl.
5. The compound according to claim 1, wherein R.sup.1 means --H;
and R.sup.2 means --C.sub.1-C.sub.6-alkyl, linear or branched,
saturated or unsaturated, unsubstituted, mono- or
polysubstituted.
6. The compound according to claim 1, wherein R.sup.1 means
--CH.sub.3; and R.sup.2 means --C.sub.1-C.sub.6-alkyl, linear or
branched, saturated or unsaturated, unsubstituted, mono- or
polysubstituted.
7. The compound according to claim 1, wherein R.sup.1 means --H or
--CH.sub.3; and wherein R.sup.2 means --CH.sub.2-cycloalkyl,
--CH.sub.2-cyclobutyl, --CH.sub.2-cyclopentyl, --CH.sub.2-oxetanyl
or --CH.sub.2-tetrahydrofuranyl.
8. The compound according to claim 1, wherein R.sup.1 and R.sup.2
together with the nitrogen atom to which they are attached form a
ring and mean --(CH.sub.2).sub.3-6--.
9. The compound according to claim 1, wherein R.sup.3 means
--C.sub.1-C.sub.6-alkyl, linear or branched, saturated or
unsaturated, unsubstituted, mono- or polysubstituted.
10. The compound according to claim 1, wherein R.sup.3 means a
6-14-membered aryl moiety, unsubstituted, mono- or
polysubstituted.
11. The compound according to claim 1, wherein R.sup.3 means a
5-14-membered heteroaryl moiety, unsubstituted, mono- or
polysubstituted.
12. The compound according to claim 1, wherein R.sup.4 means
--H.
13. The compound according to claim 1, wherein R.sup.4 means
--C.sub.1-C.sub.6-alkyl, linear or branched, saturated or
unsaturated, unsubstituted, mono- or polysubstituted.
14. The compound according to claim 1, wherein R.sup.4 means a
3-12-membered cycloalkyl moiety, saturated or unsaturated,
unsubstituted, mono- or polysubstituted; wherein the 3-12-membered
cycloalkyl moiety is connected through --C.sub.1-C.sub.6-alkylene-,
linear or branched, saturated or unsaturated, unsubstituted, mono-
or polysubstituted.
15. The compound according to claim 1, wherein R.sup.4 means a
3-12-membered heterocycloalkyl moiety, saturated or unsaturated,
unsubstituted, mono- or polysubstituted; wherein said 3-12-membered
heterocycloalkyl moiety is connected through
--C.sub.1-C.sub.6-alkylene-, linear or branched, saturated or
unsaturated, unsubstituted, mono- or polysubstituted.
16. The compound according to claim 1, wherein R.sup.4 means a
6-14-membered aryl moiety, unsubstituted, mono- or polysubstituted;
wherein said 6-14-membered aryl moiety is connected through
--C.sub.1-C.sub.6-alkylene-, linear or branched, saturated or
unsaturated, unsubstituted, mono- or polysubstituted.
17. The compound according to claim 1, wherein R.sup.4 means a
5-14-membered heteroaryl moiety, unsubstituted, mono- or
polysubstituted; wherein said 5-14-membered heteroaryl moiety is
connected through --C.sub.1-C.sub.6-alkylene-, linear or branched,
saturated or unsaturated, unsubstituted, mono- or
polysubstituted.
18. The compound according to claim 1, wherein R.sup.5 means
--H.
19. The compound according to claim 1, wherein R.sup.5 means
--C.sub.1-C.sub.6-alkyl, linear or branched, saturated or
unsaturated, unsubstituted, mono- or polysubstituted.
20. The compound according to claim 1, wherein R.sup.5 means a
3-12-membered cycloalkyl moiety, saturated or unsaturated,
unsubstituted, mono- or polysubstituted, wherein said 3-12-membered
cycloalkyl moiety is optionally connected through
--C.sub.1-C.sub.6-alkylene-, linear or branched, saturated or
unsaturated, unsubstituted, mono- or polysubstituted.
21. The compound according to claim 1, wherein R.sup.5 means a
3-12-membered heterocycloalkyl moiety, saturated or unsaturated,
unsubstituted, mono- or polysubstituted; wherein said 3-12-membered
heterocycloalkyl moiety is optionally connected through
--C.sub.1-C.sub.6-alkylene-, linear or branched, saturated or
unsaturated, unsubstituted, mono or polysubstituted.
22. The compound according to claim 1, wherein R.sup.5 means a
5-14-membered heteroaryl moiety, unsubstituted, mono- or
polysubstituted; wherein said 5-14-membered heteroaryl moiety is
optionally connected through --C.sub.1-C.sub.6-alkylene-, linear or
branched, saturated or unsaturated, unsubstituted, mono- or
polysubstituted.
23. The compound according to claim 1, wherein X means NR.sup.6 and
R.sup.5 and R.sup.6 together with the nitrogen atom to which they
are attached form a 3-12-membered heterocycloalkyl moiety,
saturated or unsaturated, unsubstituted, mono- or
polysubstituted.
24. The compound according to claim 1, wherein X means NR.sup.6 and
R.sup.6 means --H or --C.sub.1-C.sub.6-alkyl, linear or branched,
saturated or unsaturated, unsubstituted, mono- or
polysubstituted.
25. The compound according to claim 1, which has a structure
according to any of general formulas (II-A) to (VIII-C):
##STR00203## ##STR00204## ##STR00205## ##STR00206## wherein in each
case R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5, R.sup.6, R.sup.7,
R.sup.8, and X are defined as in claim 1, R.sup.C means --H, --OH,
--F, --CN or --C.sub.1-C.sub.4-alkyl; R.sup.D means --H or --F; or
a physiologically acceptable salt thereof.
26. The compound according to claim 1, wherein the substructure
##STR00207## has a meaning selected from the group consisting of:
##STR00208## ##STR00209## ##STR00210## ##STR00211##
27. The compound according to claim 1, wherein R.sup.1 means --H or
--CH.sub.3; R.sup.2 means --C.sub.1-C.sub.6-alkyl, linear or
branched, saturated, unsubstituted; R.sup.3 means -phenyl, -thienyl
or -pyridinyl, in each case unsubstituted or substituted with one,
two, three or four substituents independently of one another
selected from the group consisting of --F, --Cl, --CN, --CH.sub.3,
--CH.sub.2CH.sub.3, --CH.sub.2F, --CHF.sub.2, --CF.sub.3,
--OCF.sub.3, --OH, --OCH.sub.3, --C(.dbd.O)NH.sub.2,
C(.dbd.O)NHCH.sub.3, --C(.dbd.O)N(CH.sub.3).sub.2, --NH.sub.2,
--NHCH.sub.3, --N(CH.sub.3).sub.2, --NHC(.dbd.O)CH.sub.3,
--CH.sub.2OH, --SOCH.sub.3 and --SO.sub.2CH.sub.3; R.sup.4 means
--H; --C.sub.1-C.sub.6-alkyl, linear or branched, saturated,
unsubstituted or substituted with one, two, three or four
substituents independently of one another selected from the group
consisting of --F, --Cl, --Br, --I, --CN, --OH, and
--O--C.sub.1-C.sub.4-alkyl; 3-6-membered cycloalkyl, unsubstituted
or substituted with one, two, three or four substituents
independently of one another selected from the group consisting of
--F, --Cl, --Br, --I, --CN, --OH, and --O--C.sub.1-C.sub.4-alkyl,
wherein said 3-6-membered cycloalkyl is connected through
--C.sub.1-C.sub.6-alkylene; or 3-6-membered heterocycloalkyl,
unsubstituted or substituted with one, two, three or four
substituents independently of one another selected from the group
consisting of --F, --Cl, --Br, --I, --CN, --OH, and
--O--C.sub.1-C.sub.4-alkyl, wherein said 3-6-membered
heterocycloalkyl is connected through --C.sub.1-C.sub.6-alkylene; X
means --O-- or --NR.sup.6--; R.sup.5 means --H;
--C.sub.1-C.sub.6-alkyl, linear or branched, saturated or
unsaturated, unsubstituted or substituted with one, two, three or
four substituents independently of one another selected from the
group consisting of --F, --Cl, --Br, --I, --CN,
--O--C.sub.1-C.sub.4-alkyl, --C(.dbd.O)OH,
--C(.dbd.O)OC.sub.1-C.sub.4-alkyl, --C(.dbd.O)NH.sub.2,
--C(.dbd.O)NHC.sub.1-C.sub.4-alkyl,
--C(.dbd.O)N(C.sub.1-C.sub.4-alkyl).sub.2, --OH,
--S(.dbd.O)C.sub.1-C.sub.4-alkyl and --S(.dbd.O).sub.2
C.sub.1-C.sub.4-alkyl; -cyclobutyl, unsubstituted or
monosubstituted with --OH; wherein said -cyclobutyl is connected
through --CH.sub.2--; -heterocyclobutyl, unsubstituted; or
-oxazolyl, -pyridinyl, -pyridazinyl or -pyrimidinyl, in each case
unsubstituted or substituted with one, two, three or four
substituents independently of one another selected from the group
consisting of --F, --Cl, Br, --I, --OH, --O--C.sub.1-C.sub.4-alkyl,
--CN, and --S(.dbd.O).sub.2C.sub.1-C.sub.4-alkyl; wherein said
-oxazolyl, -pyridinyl, -pyridazinyl or -pyrimidinyl is optionally
connected through --CH.sub.2--; in case X means NR.sup.6, R.sup.6
means --H or --CH.sub.3; or in case X means NR.sup.6, R.sup.5 and
R' together with the nitrogen atom to which they are attached form
a piperidine moiety, a pyrrolidine moiety, a morpholine moiety, a
thiomorpholine moiety, a thiomorpholine dioxide moiety, or a
piperazine moiety, in each case unsubstituted or substituted with
one, two, three or four substituents independently of one another
selected from the group consisting of .dbd.O, --OH, and
--C(.dbd.O)NH.sub.2; wherein said piperidine moiety, pyrrolidine
moiety, morpholine moiety, thiomorpholine moiety, thiomorpholine
dioxide moiety, or piperazine moiety is optionally condensed with
an imidazole moiety, unsubstituted; R.sup.7 and R.sup.8
independently of one another mean --H or --CH.sub.3; or R.sup.7 and
R.sup.8 together with the carbon atom to which they are attached
form a ring selected from the group consisting of cyclopropyl,
cyclobutyl, heterocyclobutyl and heterocyclohexyl, in each case
unsubstituted; and R.sup.9, R.sup.10, R.sup.11, R.sup.12, R.sup.13,
R.sup.14, R.sup.15, R.sup.16, R.sup.17, R.sup.18, R.sup.19, and
R.sup.20 mean --H.
28. The compound according to claim 1, which has a structure
according to general formula (I') ##STR00212## wherein R.sup.1 to
R.sup.5, R.sup.7 to R.sup.20, and X are defined as in claim 1, or a
physiologically acceptable salt thereof.
29. The compound according to claim 1, which has a structure
according to general formula (IX) ##STR00213## wherein R.sup.C
means --H or --OH; R.sup.D means --H or --F; R.sup.5 means --H,
--CH.sub.3, or --CH.sub.2CH.sub.2--OH; R.sup.6 means --H or
--CH.sub.3; and R.sup.7 means --CH.sub.3 and R.sup.8 means
--CH.sub.3; or R.sup.7 and R.sup.8 together with the carbon atom to
which they are attached form a cyclopropyl ring; or a
physiologically acceptable salt thereof.
30. The compound according to claim 1, which is selected from the
group consisting of
CIS-3-[8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-2-oxo-8-phenyl-1-
,3-diazaspiro[4.5]decan-3-yl]-N-pyridazin-3-yl-propionamide;
CIS-3-[8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-2-oxo-8-phenyl-1-
,3-diazaspiro[4.5]decan-3-yl]-propionamide;
CIS-3-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspir-
o[4.5]decan-3-yl]-N-(2-methoxy-pyridin-4-yl)-propionamide;
CIS-3-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspir-
o[4.5]decan-3-yl]-N-(6-methoxy-pyridin-3-yl)-propionamide;
CIS-3-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspir-
o[4.5]decan-3-yl]-N-(3-methoxy-pyridin-4-yl)-propionamide;
CIS-3-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspir-
o[4.5]decan-3-yl]-N-(6-methoxy-pyridazin-3-yl)-propionamide;
CIS-3-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspir-
o[4.5]decan-3-yl]-N-(5-methylsulfonyl-pyridin-2-yl)-propionamide;
CIS-3-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspir-
o[4.5]decan-3-yl]-N-(5-methoxy-pyridin-2-yl)-propionamide;
CIS-3-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspir-
o[4.5]decan-3-yl]-N-(6-methylsulfonyl-pyridin-3-yl)-propionamide;
CIS-3-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspir-
o[4.5]decan-3-yl]-N-(6-methoxy-pyrazin-2-yl)-propionamide;
CIS-3-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspir-
o[4.5]decan-3-yl]-N-(4-methoxy-pyridin-2-yl)-propionamide;
CIS-3-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspir-
o[4.5]decan-3-yl]-N-(oxazol-5-yl-methyl)-propionamide;
CIS-3-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspir-
o[4.5]decan-3-yl]-N-(oxazol-2-yl-methyl)-propionamide;
CIS-1-(Cyclobutyl-methyl)-3-[3-[3,4-dihydroxy-piperidin-1-yl]-3-oxo-propy-
l]-8-dimethylamino-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;
CIS-1-(Cyclobutyl-methyl)-3-[3-[3,4-dihydroxy-pyrrolidin-1-yl]-3-oxo-prop-
yl]-8-dimethylamino-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;
CIS-1-(Cyclobutyl-methyl)-3-[3-[(3
S,4R)-3,4-dihydroxy-pyrrolidin-1-yl]-3-oxo-propyl]-8-dimethylamino-8-phen-
yl-1,3-diazaspiro[4.5]decan-2-one;
CIS-1-(Cyclobutyl-methyl)-8-dimethylamino-3-[3-(3-hydroxy-piperidin-1-yl)-
-3-oxo-propyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;
CIS-3-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspir-
o[4.5]decan-3-yl]-N-[(1-hydroxy-cyclobutyl)-methyl]-propionamide;
CIS-1-(Cyclobutyl-methyl)-8-dimethylamino-3-[3-oxo-3-(5,6,7,8-tetrahydro--
[1,2,4]triazolo[1,5-a]pyrazin-7-yl)-propyl]-8-phenyl-1,3-diazaspiro[4.5]de-
can-2-one;
CIS-3-[3-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl--
1,3-diazaspiro[4.5]decan-3-yl]-propanoylamino]-N,N-dimethyl-propionamide;
CIS-N-(2-Cyano-pyrimidin-5-yl)-3-[8-dimethylamino-1-[(1-hydroxy-cyclobuty-
l)-methyl]-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-propionamide;
CIS-3-[8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-2-oxo-8-phenyl-1-
,3-diazaspiro[4.5]decan-3-yl]-N-pyrimidin-2-yl-propionamide;
CIS-3-[8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-2-oxo-8-phenyl-1-
,3-diazaspiro[4.5]decan-3-yl]-N-(4-hydroxy-pyrimidin-2-yl)-propionamide;
CIS-3-[8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-2-oxo-8-phenyl-1-
,3-diazaspiro[4.5]decan-3-yl]-N-(4-methoxy-pyrimidin-2-yl)-propionamide;
CIS-3-[1-(Cyclobutyl-methyl)-8-methylamino-2-oxo-8-phenyl-1,3-diazaspiro[-
4.5]decan-3-yl]-2,2-dimethyl-propionamide;
CIS-3-[1-[(1-Hydroxy-cyclobutyl)-methyl]-8-methylamino-2-oxo-8-phenyl-1,3-
-diazaspiro[4.5]decan-3-yl]-N-(2-hydroxy-ethyl)-propionamide;
CIS-3-[1-[(1-Hydroxy-cyclobutyl)-methyl]-8-methylamino-2-oxo-8-phenyl-1,3-
-diazaspiro[4.5]decan-3-yl]-propionamide;
CIS-3-[1-[(1-Hydroxy-cyclobutyl)-methyl]-8-methylamino-2-oxo-8-phenyl-1,3-
-diazaspiro[4.5]decan-3-yl]-N-methyl-propionamide;
CIS-3-[1-[(1-Hydroxy-cyclobutyl)-methyl]-8-methylamino-2-oxo-8-phenyl-1,3-
-diazaspiro[4.5]decan-3-yl]-N-pyridazin-3-yl-propionamide;
CIS-3-[8-Dimethylamino-1-(2-methoxy-ethyl)-2-oxo-8-phenyl-1,3-diazaspiro[-
4.5]decan-3-yl]-N-(2-hydroxy-ethyl)-propionamide;
CIS-3-[8-Dimethylamino-1-(2-methoxy-ethyl)-2-oxo-8-phenyl-1,3-diazaspiro[-
4.5]decan-3-yl]-N-methyl-propionamide;
CIS-3-[8-Dimethylamino-1-(2-methoxy-ethyl)-2-oxo-8-phenyl-1,3-diazaspiro[-
4.5]decan-3-yl]-N-pyrimidin-5-yl-propionamide;
CIS-3-[8-Dimethylamino-1-(3-methoxy-propyl)-2-oxo-8-phenyl-1,3-diazaspiro-
[4.5]decan-3-yl]-2,2-dimethyl-propionamide;
CIS-3-[8-Dimethylamino-1-(2-methoxy-ethyl)-2-oxo-8-phenyl-1,3-diazaspiro[-
4.5]decan-3-yl]-2,2-dimethyl-propionamide;
CIS-3-[8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-2-oxo-8-phenyl-1-
,3-diazaspiro[4.5]decan-3-yl]-N-pyridin-3-yl-propionamide;
CIS-3-[8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-2-oxo-8-phenyl-1-
,3-diazaspiro[4.5]decan-3-yl]-N-pyridin-4-yl-propionamide;
CIS-2-[3-[8-Dimethylamino-1-(3-methoxy-propyl)-2-oxo-8-phenyl-1,3-diazasp-
iro[4.5]decan-3-yl]-propanoylamino]-2-methyl-propionamide;
CIS-3-[8-Dimethylamino-1-(3-methoxy-propyl)-2-oxo-8-phenyl-1,3-diazaspiro-
[4.5]decan-3-yl]-N-(2-methylsulfonyl-ethyl)-propionamide;
CIS-3-[8-Dimethylamino-1-(3-methoxy-propyl)-2-oxo-8-phenyl-1,3-diazaspiro-
[4.5]decan-3-yl]-N-(2-hydroxy-ethyl)-propionamide;
CIS-8-Dimethylamino-1-(3-methoxy-propyl)-3-[3-oxo-3-(3-oxo-piperazin-1-yl-
)-propyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;
CIS-(2R)-1-[3-[8-Dimethylamino-1-(3-methoxy-propyl)-2-oxo-8-phenyl-1,3-di-
azaspiro[4.5]decan-3-yl]-propanoyl]-pyrrolidine-2-carboxylic acid
amide;
CIS-N-(Carbamoyl-methyl)-3-[8-dimethylamino-1-(3-methoxy-propyl)-2-oxo-8--
phenyl-1,3-diazaspiro[4.5]decan-3-yl]-propionamide;
CIS-3-[8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-2-oxo-8-phenyl-1-
,3-diazaspiro[4.5]decan-3-yl]-N-pyridin-2-yl-propionamide;
CIS-3-[1-(Cyclobutyl-methyl)-8-(ethyl-methyl-amino)-2-oxo-8-phenyl-1,3-di-
azaspiro[4.5]decan-3-yl]-2,2-dimethyl-propionamide;
CIS-3-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspir-
o[4.5]decan-3-yl]-2,2-dimethyl-propionamide;
CIS-3-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspir-
o[4.5]decan-3-yl]-propionamide;
CIS-3-[8-Dimethylamino-1-(2-methoxy-ethyl)-2-oxo-8-phenyl-1,3-diazaspiro[-
4.5]decan-3-yl]-diazaspiro[4.5]decan-3-yl]-N-methyl-propionamide;
CIS-3-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspir-
o[4.5]decan-3-yl]-N-methyl-propionamide;
CIS-3-[8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-2-oxo-8-phenyl-1-
,3-diazaspiro[4.5]decan-3-yl]-N-pyrimidin-5-yl-propionamide;
CIS-3-[8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-2-oxo-8-phenyl-1-
,3-diazaspiro[4.5]decan-3-yl]-N-methyl-propionamide;
CIS-3-[8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-2-oxo-8-phenyl-1-
,3-diazaspiro[4.5]decan-3-yl]-N-(2-hydroxy-ethyl)-propionamide;
CIS-3-[8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-2-oxo-8-phenyl-1-
,3-diazaspiro[4.5]decan-3-yl]-N-(2-hydroxy-ethyl)-propionamide;
CIS-3-[8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-2-oxo-8-phenyl-1-
,3-diazaspiro[4.5]decan-3-yl]-N-(oxetan-3-yl)-propionamide;
CIS-N-(Carbamoyl-methyl)-3-[1-(cyclobutyl-methyl)-8-dimethyl-amino-2-oxo--
8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-2,2-dimethyl-propionamide;
CIS-N-(Carbamoyl-methyl)-3-[1-(cyclobutyl-methyl)-8-methylamino-2-oxo-8-p-
henyl-1,3-diazaspiro[4.5]decan-3-yl]-2,2-dimethyl-propionamide;
CIS-3-[8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-2-oxo-8-phenyl-1-
,3-diazaspiro[4.5]decan-3-yl]-2,2-dimethyl-propionamide;
CIS-3-[1-[(1-Hydroxy-cyclobutyl)-methyl]-8-methylamino-2-oxo-8-phenyl-1,3-
-diazaspiro[4.5]decan-3-yl]-N-(oxetan-3-yl)-propionamide;
CIS-3-[1-[(1-Hydroxy-cyclobutyl)-methyl]-8-methylamino-2-oxo-8-phenyl-1,3-
-diazaspiro[4.5]decan-3-yl]-2,2-dimethyl-propionamide;
CIS-3-[8-(Ethyl-methyl-amino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-y-
l]-2,2-dimethyl-propionamide;
CIS-3-[8-(Ethyl-methyl-amino)-1-methyl-2-oxo-8-phenyl-1,3-diazaspiro[4.5]-
decan-3-yl]-2,2-dimethyl-propionamide;
CIS-2,2-Dimethyl-3-(8-methylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-
-3-yl)-propionamide;
CIS-3-(8-Ethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-2,2-dim-
ethyl-propionamide;
CIS-3-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-2,2--
dimethyl-propionamide;
CIS-3-[1-(Cyclobutyl-methyl)-8-ethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4-
.5]decan-3-yl]-2,2-dimethyl-propionamide;
CIS-3-[8-Dimethylamino-1-(oxetan-3-yl-methyl)-2-oxo-8-phenyl-1,3-diazaspi-
ro[4.5]decan-3-yl]-2,2-dimethyl-propionamide; CIS-3-[1
(Cyclopropyl-methy)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]dec-
an-3-yl]-2,2-dimethyl-propionamide;
CIS-3-[8-(Ethyl-methyl-amino)-1-[(1-hydroxy-cyclobutyl)-methyl]-2-oxo-8-p-
henyl-1,3-diazaspiro[4.5]decan-3-yl]-2,2-dimethyl-propionamide;
CIS-8-Dimethylamino-3-(2,2-dimethyl-3-morpholin-4-yl
-3-oxo-propyl)-1-[(1-hydroxy-cyclobutyl)-methyl]-8-phenyl-1,3-diazaspiro[-
4.5]decan-2-one;
CIS-3-[8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-2-oxo-8-phenyl-1-
,3-diazaspiro[4.5]decan-3-yl]-N-(2-hydroxy-ethyl)-2,2-dimethyl-propionamid-
e;
CIS-3-[1-[(1-Cyano-cyclobutyl)-methyl]-8-dimethylamino-2-oxo-8-phenyl-1-
,3-diazaspiro[4.5]decan-3-yl]-2,2-dimethyl-propionamide;
CIS-8-Dimethylamino-3-[3-(1,1-dioxo-[1,4]thiazinan-4-yl)-2,2-dimethyl-3-o-
xo-propyl]-1-[(1-hydroxy-cyclobutyl)-methyl]-8-phenyl-1,3-diazaspiro[4.5]d-
ecan-2-one;
TRANS-3-[8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-2-oxo-8-phenyl-
-1,3-diazaspiro[4.5]decan-3-yl]-2,2-dimethyl-propionamide
TRANS-3-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-2,-
2-dimethyl-propionamide;
CIS-3-[1-(Cyclopropyl-methyl)-8-dimethylamino-8-(3-fluorophenyl)-2-oxo-1,-
3-diazaspiro[4.5]decan-3-yl]-N,N-dimethyl-propionamide;
CIS-3-[1-(Cyclopropyl-methyl)-8-dimethylamino-8-(3-fluorophenyl)-2-oxo-1,-
3-diazaspiro[4.5]decan-3-yl]-2,2-dimethyl-propionamide;
CIS-1-((1-(cyclopropylmethyl)-8-(dimethylamino)-2-oxo-8-phenyl-1,3-diazas-
piro[4.5]decan-3-yl)methyl)cyclopropanecarboxamide;
CIS-3-((1-(cyclopropylmethyl)-8-(dimethylamino)-2-oxo-8-phenyl-1,3-diazas-
piro[4.5]decan-3-yl)methyl)oxetane-3-carboxamide;
CIS-3-(1-(cyclopropylmethyl)-8-(methylamino)-2-oxo-8-phenyl-1,3-diazaspir-
o[4.5]decan-3-yl)-2,2-dimethylpropanamide;
CIS-3-(1-(cyclopropylmethyl)-8-(dimethylamino)-2-oxo-8-phenyl-1,3-diazasp-
iro[4.5]decan-3-yl)propanamide;
CIS-3-(8-(dimethylamino)-1-((1-fluorocyclopropyl)methyl)-2-oxo-8-phenyl-1-
,3-diazaspiro[4.5]decan-3-yl)-2,2-dimethylpropanamide and the
physiologically acceptable salts thereof.
31. The compound according to claim 1 for use in the treatment of
pain.
32. A medicament comprising a compound according to claim 1.
33. A method of treating pain in a subject in need thereof, said
method comprising administering to said subject an effective amount
therefor of at least one compound according to claim 1.
Description
[0001] This application is a continuation of U.S. Non-Provisional
patent application Ser. No. 15/405,482 filed Jan. 13, 2017, which
claims foreign priority of European Patent Application No. 16 151
011.0, filed Jan. 13, 2016, the disclosures of which are
incorporated herein by reference.
[0002] The invention relates to
3-(carboxyethyl)-8-amino-2-oxo-1,3-diaza-spiro-[4.5]-decane
derivatives, their preparation and use in medicine, particularly in
various neurological disorders, including but not limited to pain,
neurodegenerative disorders, neuroinflammatory disorders,
neuropsychiatric disorders, substance abuse/dependence.
[0003] Opioid receptors are a group of Gi/o protein-coupled
receptors which are widely distributed in the human body. The
opioid receptors are currently subdivided into four major classes,
i.e. the three classical opioid receptors mu-opioid (MOP) receptor,
kappa-opioid (KOP) receptor, and delta-opioid (DOP) receptor as
well as the opioid receptor-like (ORL-1) receptor, which was more
recently discovered based on its high homology with said classical
opioid receptors. After identification of the endogenous ligand of
the ORL-1 receptor, known as nociceptin/orphanin FQ, a highly basic
17 amino acid peptide isolated from tissue extracts in 1995, the
ORL-1 receptor was renamed "nociceptin opioid peptide receptor" and
abbreviated as "NOP-receptor".
[0004] The classical opioid receptors (MOP, KOP and DOP) as well as
the NOP receptor are widely distributed/expressed in the human
body, including in the brain, the spinal cord, on peripheral
sensory neurons and the intestinal tract, wherein the distribution
pattern differs between the different receptor classes.
[0005] Nociceptin acts at the molecular and cellular level in very
much the same way as opioids. However, its pharmacological effects
sometimes differ from, and even oppose those of opioids.
NOP-receptor activation translates into a complex pharmacology of
pain modulation, which, depending on route of administration, pain
model and species involved, leads to either pronociceptive or
antinociceptive activity. Furthermore, the NOP receptor system is
upregulated under conditions of chronic pain. Systemic
administration of selective NOP receptor agonists was found to
exert a potent and efficacious analgesia in non-human primate
models of acute and inflammatory pain in the absence of side
effects. The activation of NOP receptors has been demonstrated to
be devoid of reinforcing effects but to inhibit opioid-mediated
reward in rodents and non-human primates (Review: Schroeder et al,
Br J Pharmacol 2014; 171 (16): 3777-3800, and references
therein).
[0006] Besides the involvement of the NOP receptor in nociception,
results from preclinical experiments suggest that NOP receptor
agonists might be useful inter alia in the treatment of
neuropsychiatric disorders (Witkin et al, Pharmacology &
Therapeutics, 141 (2014) 283-299; Jenck et al., Proc. Natl. Acad.
Sci. USA 94, 1997, 14854-14858). Remarkably, the DOP receptor is
also implicated to modulate not only pain but also neuropsychiatric
disorders (Mabrouk et al, 2014; Pradhan et al., 2011).
[0007] Strong opioids acting at the MOP receptor site are widely
used to treat moderate to severe acute and chronic pain. However,
the therapeutic window of strong opioids is limited by severe side
effects such as nausea and vomiting, constipation, dizziness,
somnolence, respiratory depression, physical dependence and abuse.
Furthermore, it is known that MOP receptor agonists show only
reduced effectiveness under conditions of chronic and neuropathic
pain.
[0008] It is known that some of the above mentioned side-effects of
strong opioids are mediated by activation of classic
opioid-receptors within the central nervous system. Furthermore,
peripheral opioid receptors, when activated, can inhibit
transmission of nociceptive signals shown in both, clinical and
animal studies (Gupta et al., 2001; Kalso et al., 2002; Stein et
al., 2003; Zollner et al., 2008).
[0009] Thus, to avoid CNS-mediated adverse effects after systemic
administration, one approach has been to provide peripherally
restricted opioid receptor ligands that do not easily cross the
blood-brain barrier and therefore distribute poorly to the central
nervous system (see for instance WO 2015/192039). Such peripherally
acting compounds might combine effective analgesia with limited
side-effects.
[0010] Another approach has been to provide compounds which
interact with both the NOP receptor and the MOP receptor. Such
compounds have for instance been described in WO 2004/043967, WO
2012/013343 and WO 2009/118168.
[0011] A further approach has been to provide multi-opioid receptor
analgesics that modulate more than one of the opioid receptor
subtypes to provide additive or synergistic analgesia and/or
reduced side effects like abuse liability or tolerance.
[0012] On the one hand, it would be desirable to provide analgesics
that selectively act on the NOP receptor system but less pronounced
on the classic opioid receptor system, especially MOP receptor
system, whereas it would be desirable to distinguish between
central nervous activity and peripheral nervous activity. On the
other hand, it would be desirable to provide analgesics that act on
the NOP receptor system and also to a balanced degree on the MOP
receptor system, whereas it would be desirable to distinguish
between central nervous activity and peripheral nervous
activity.
[0013] There is a need for medicaments which are effective in the
treatment of pain and which have advantages compared to the
compounds of the prior art. Where possible, such medicaments should
contain such a small dose of active ingredient that satisfactory
pain therapy can be ensured without the occurrence of intolerable
treatment-emergent adverse events.
[0014] It is an object of the invention to provide
pharmacologically active compounds, preferably analgesics that have
advantages compared to the prior art.
[0015] This object has been achieved by the subject-matter of the
patent claims.
[0016] A first aspect of the invention relates to
3-(carboxyethyl)-8-amino-2-oxo-1,3-diaza-spiro-[4.5]-decane
derivatives according to general formula (I)
##STR00001##
wherein R.sup.1 and R.sup.2 independently of one another mean
--H;
[0017] --C.sub.1-C.sub.6-alkyl, linear or branched, saturated or
unsaturated, unsubstituted or substituted with one, two, three or
four substituents independently of one another selected from the
group consisting of --F, --Cl, --Br, --I, --OH, --OCH.sub.3, --CN
and --CO.sub.2CH.sub.3; a 3-12-membered cycloalkyl moiety,
saturated or unsaturated, unsubstituted or substituted with one,
two, three or four substituents independently of one another
selected from the group consisting of --F, --Cl, --Br, --I, --OH,
--OCH.sub.3, --CN and --CO.sub.2CH.sub.3; wherein said
3-12-membered cycloalkyl moiety is optionally connected through
--C.sub.1-C.sub.6-alkylene-, linear or branched, saturated or
unsaturated, unsubstituted; or a 3-12-membered heterocycloalkyl
moiety, saturated or unsaturated, unsubstituted or substituted with
one, two, three or four substituents independently of one another
selected from the group consisting of --F, --Cl, --Br, --I, --OH,
--OCH.sub.3, --CN and --CO.sub.2CH.sub.3; wherein said
3-12-membered heterocycloalkyl moiety is optionally connected
through --C.sub.1-C.sub.6-alkylene-, linear or branched, saturated
or unsaturated, unsubstituted; or R.sup.1 and R.sup.2 together with
the nitrogen atom to which they are attached form a ring and mean
--(CH.sub.2).sub.3-6--; --(CH.sub.2).sub.2--O--(CH.sub.2).sub.2--;
or --(CH.sub.2).sub.2--NR.sup.A--(CH.sub.2).sub.2--, wherein
R.sup.A means --H or --C.sub.1-C.sub.6-alkyl, linear or branched,
saturated or unsaturated, unsubstituted or substituted with one,
two, three or four substituents independently of one another
selected from the group consisting of --F, --Cl, --Br and --I;
preferably with the proviso that R.sup.1 and R.sup.2 do not
simultaneously mean --H; R.sup.3 means --C.sub.1-C.sub.6-alkyl,
linear or branched, saturated or unsaturated, unsubstituted, mono-
or polysubstituted; a 3-12-membered cycloalkyl moiety, saturated or
unsaturated, unsubstituted, mono- or polysubstituted; wherein said
3-12-membered cycloalkyl moiety is optionally connected through
--C.sub.1-C.sub.6-alkylene-, linear or branched, saturated or
unsaturated, unsubstituted, mono- or polysubstituted; a
3-12-membered heterocycloalkyl moiety, saturated or unsaturated,
unsubstituted, mono- or polysubstituted; wherein said 3-12-membered
heterocycloalkyl moiety is optionally connected through
--C.sub.1-C.sub.6-alkylene-, linear or branched, saturated or
unsaturated, unsubstituted, mono- or polysubstituted; a
6-14-membered aryl moiety, unsubstituted, mono- or polysubstituted;
wherein said 6-14-membered aryl moiety is optionally connected
through --C.sub.1-C.sub.6-alkylene-, linear or branched, saturated
or unsaturated, unsubstituted, mono- or polysubstituted; or a
5-14-membered heteroaryl moiety, unsubstituted, mono- or
polysubstituted; wherein said 5-14-membered heteroaryl moiety is
optionally connected through --C.sub.1-C.sub.6-alkylene-, linear or
branched, saturated or unsaturated, unsubstituted, mono- or
polysubstituted; R.sup.4 means
--H;
[0018] --C.sub.1-C.sub.6-alkyl, linear or branched, saturated or
unsaturated, unsubstituted, mono- or polysubstituted; wherein said
--C.sub.1-C.sub.6-alkyl is optionally connected through
--C(.dbd.O)--, --C(.dbd.O)O--, or --S(.dbd.O).sub.2--; a
3-12-membered cycloalkyl moiety, saturated or unsaturated,
unsubstituted, mono- or polysubstituted; wherein said 3-12-membered
cycloalkyl moiety is optionally connected through
--C.sub.1-C.sub.6-alkylene-, linear or branched, saturated or
unsaturated, unsubstituted, mono- or polysubstituted; or wherein
said 3-12-membered cycloalkyl moiety is optionally connected
through --C(.dbd.O)--, --C(.dbd.O)O--, --C(.dbd.O)O--CH.sub.2--, or
--S(.dbd.O).sub.2--; a 3-12-membered heterocycloalkyl moiety,
saturated or unsaturated, unsubstituted, mono- or polysubstituted;
wherein said 3-12-membered heterocycloalkyl moiety is optionally
connected through --C.sub.1-C.sub.6-alkylene-, linear or branched,
saturated or unsaturated, unsubstituted, mono- or polysubstituted;
or wherein said 3-12-membered heterocycloalkyl moiety is optionally
connected through --C(.dbd.O)--, --C(.dbd.O)O--,
--C(.dbd.O)O--CH.sub.2--, or --S(.dbd.O).sub.2--; a 6-14-membered
aryl moiety, unsubstituted, mono- or polysubstituted; wherein said
6-14-membered aryl moiety is optionally connected through
--C.sub.1-C.sub.6-alkylene-, linear or branched, saturated or
unsaturated, unsubstituted, mono- or polysubstituted or wherein
said 6-14-membered aryl moiety is optionally connected through
--C(.dbd.O)--, --C(.dbd.O)O--, --C(.dbd.O)O--CH.sub.2--, or
--S(.dbd.O).sub.2--; or a 5-14-membered heteroaryl moiety,
unsubstituted, mono- or polysubstituted; wherein said 5-14-membered
heteroaryl moiety is optionally connected through
--C.sub.1-C.sub.6-alkylene-, linear or branched, saturated or
unsaturated, unsubstituted, mono- or polysubstituted; or wherein
said 5-14-membered heteroaryl moiety is optionally connected
through --C(.dbd.O)--, --C(.dbd.O)O--, --C(.dbd.O)O--CH.sub.2--, or
--S(.dbd.O).sub.2--; X means --O--, --S-- or --NR.sup.6--; R.sup.5
means
--H;
[0019] --C.sub.1-C.sub.6-alkyl, linear or branched, saturated or
unsaturated, unsubstituted, mono- or polysubstituted; a
3-12-membered cycloalkyl moiety, saturated or unsaturated,
unsubstituted, mono- or polysubstituted; wherein said 3-12-membered
cycloalkyl moiety is optionally connected through
--C.sub.1-C.sub.6-alkylene-, linear or branched, saturated or
unsaturated, unsubstituted, mono- or polysubstituted; a
3-12-membered heterocycloalkyl moiety, saturated or unsaturated,
unsubstituted, mono- or polysubstituted; wherein said 3-12-membered
heterocycloalkyl moiety is optionally connected through
--C.sub.1-C.sub.6-alkylene-, linear or branched, saturated or
unsaturated, unsubstituted, mono- or polysubstituted; a
6-14-membered aryl moiety, unsubstituted, mono- or polysubstituted;
wherein said 6-14-membered aryl moiety is optionally connected
through --C.sub.1-C.sub.6-alkylene-, linear or branched, saturated
or unsaturated, unsubstituted, mono- or polysubstituted; or a
5-14-membered heteroaryl moiety, unsubstituted, mono- or
polysubstituted; wherein said 5-14-membered heteroaryl moiety is
optionally connected through --C.sub.1-C.sub.6-alkylene-, linear or
branched, saturated or unsaturated, unsubstituted, mono- or
polysubstituted; in case X means NR.sup.6, R.sup.6 means
--H;
[0020] --C.sub.1-C.sub.6-alkyl, linear or branched, saturated or
unsaturated, unsubstituted, mono- or polysubstituted; a
3-12-membered cycloalkyl moiety, saturated or unsaturated,
unsubstituted, mono- or polysubstituted; wherein said 3-12-membered
cycloalkyl moiety is optionally connected through
--C.sub.1-C.sub.6-alkylene-, linear or branched, saturated or
unsaturated, unsubstituted, mono- or polysubstituted; a
3-12-membered heterocycloalkyl moiety, saturated or unsaturated,
unsubstituted, mono- or polysubstituted; wherein said 3-12-membered
heterocycloalkyl moiety is optionally connected through
--C.sub.1-C.sub.6-alkylene-, linear or branched, saturated or
unsaturated, unsubstituted, mono- or polysubstituted; a
6-14-membered aryl moiety, unsubstituted, mono- or polysubstituted;
wherein said 6-14-membered aryl moiety is optionally connected
through --C.sub.1-C.sub.6-alkylene-, linear or branched, saturated
or unsaturated, unsubstituted, mono- or polysubstituted; or a
5-14-membered heteroaryl moiety, unsubstituted, mono- or
polysubstituted; wherein said 5-14-membered heteroaryl moiety is
optionally connected through --C.sub.1-C.sub.6-alkylene-, linear or
branched, saturated or unsaturated, unsubstituted, mono- or
polysubstituted; or in case X means NR.sup.6, R.sup.5 and R.sup.6
together with the nitrogen atom to which they are attached form a
3-12-membered heterocycloalkyl moiety, saturated or unsaturated,
unsubstituted, mono- or polysubstituted; R.sup.7, R.sup.8, R.sup.9,
R.sup.10, R.sup.11, R.sup.12, R.sup.13, R.sup.14, R.sup.15,
R.sup.16, R.sup.17, R.sup.18, R.sup.19, and R.sup.20 independently
of one another mean --H, --F, --Cl, --Br, --I, --OH, or
--C.sub.1-C.sub.6-alkyl, linear or branched, saturated or
unsaturated, unsubstituted, mono- or polysubstituted; or R.sup.7
and R.sup.8 together with the carbon atom to which they are
attached form a 3-12-membered cycloalkyl moiety, saturated or
unsaturated, unsubstituted, mono- or polysubstituted; or a
3-12-membered heterocycloalkyl moiety, saturated or unsaturated,
unsubstituted, mono- or polysubstituted; wherein "mono- or
polysubstituted" means that one or more hydrogen atoms are replaced
by a substituent independently of one another selected from the
group consisting of --F, --Cl, --Br, --I, --CN, --R.sup.21,
--C(.dbd.O)R.sup.21, --C(.dbd.O)OR.sup.21,
--C(.dbd.O)NR.sup.21R.sup.22,
--O--(CH.sub.2CH.sub.2--O).sub.1-30--H,
--O--(CH.sub.2CH.sub.2--O).sub.1-30--CH.sub.3, .dbd.O, --OR.sup.21,
--OC(.dbd.O)R.sup.21, --OC(.dbd.O)OR.sup.21,
--OC(.dbd.O)NR.sup.21R.sup.22, --NO.sub.2, --NR.sup.21R.sup.22,
--NR.sup.21--(CH.sub.2).sub.1-6--C(.dbd.O)R.sup.22,
NR.sup.21--(CH.sub.2).sub.1-6--C(.dbd.O)OR.sup.22,
--NR.sup.23--(CH.sub.2).sub.6--C(.dbd.O)NR.sup.21R.sup.22,
--NR.sup.21C(.dbd.O)R.sup.22, --NR.sup.21C(.dbd.O)--OR.sup.22,
NR.sup.23C(.dbd.O)NR.sup.21R.sup.22,
--NR.sup.21S(.dbd.O).sub.2R.sup.22, --SR.sup.21,
--S(.dbd.O)R.sup.21, --S(.dbd.O).sub.2R.sup.21,
--S(.dbd.O).sub.2OR.sup.21, and --S(.dbd.O).sub.2NR.sup.21R.sup.22;
wherein R.sup.21, R.sup.22 and R.sup.23 independently of one
another mean
--H;
[0021] --C.sub.1-C.sub.6-alkyl, linear or branched, saturated or
unsaturated, unsubstituted or substituted with one, two, three or
four substituents independently of one another selected from the
group consisting of --F, --Cl, --Br, --I, --CN, --OH, --NH.sub.2,
and --O--C.sub.1-C.sub.6-alkyl; a 3-12-membered cycloalkyl moiety,
saturated or unsaturated, unsubstituted; wherein said 3-12-membered
cycloalkyl moiety is optionally connected through
--C.sub.1-C.sub.6-alkylene-, linear or branched, saturated or
unsaturated, unsubstituted or substituted with one, two, three or
four substituents independently of one another selected from the
group consisting of --F, --Cl, --Br, --I, --CN, --OH, --NH.sub.2,
--C.sub.1-C.sub.6-alkyl and --O--C.sub.1-C.sub.6-alkyl; a
3-12-membered heterocycloalkyl moiety, saturated or unsaturated,
unsubstituted; wherein said 3-12-membered heterocycloalkyl moiety
is optionally connected through --C.sub.1-C.sub.6-alkylene-, linear
or branched, saturated or unsaturated, unsubstituted or substituted
with one, two, three or four substituents independently of one
another selected from the group consisting of --F, --Cl, --Br, --I,
--CN, --OH, --NH.sub.2, --C.sub.1-C.sub.6-alkyl and
--O--C.sub.1-C.sub.6-alkyl; a 6-14-membered aryl moiety,
unsubstituted, mono- or polysubstituted; wherein said 6-14-membered
aryl moiety is optionally connected through
--C.sub.1-C.sub.6-alkylene-, linear or branched, saturated or
unsaturated, unsubstituted or substituted with one, two, three or
four substituents independently of one another selected from the
group consisting of --F, --Cl, --Br, --I, --CN, --OH, --NH.sub.2,
--C.sub.1-C.sub.6-alkyl and --O--C.sub.1-C.sub.6-alkyl; a
5-14-membered heteroaryl moiety, unsubstituted, mono- or
polysubstituted; wherein said 5-14-membered heteroaryl moiety is
optionally connected through --C.sub.1-C.sub.6-alkylene-, linear or
branched, saturated or unsaturated, unsubstituted or substituted
with one, two, three or four substituents independently of one
another selected from the group consisting of --F, --Cl, --Br, --I,
--CN, --OH, --NH.sub.2, --C.sub.1-C.sub.6-alkyl and
--O--C.sub.1-C.sub.6-alkyl; or R.sup.21 and R.sup.22 within
--C(.dbd.O)NR.sup.21R.sup.22, --OC(.dbd.O)NR.sup.21R.sup.22,
--NR.sup.21R.sup.22,
--NR.sup.23--(CH.sub.2).sub.1-6--C(.dbd.O)NR.sup.21R.sup.22,
NR.sup.23C(.dbd.O)NR.sup.21R.sup.22, or
--S(.dbd.O).sub.2NR.sup.21R.sup.22 together with the nitrogen atom
to which they are attached form a ring and mean
--(CH.sub.2).sub.3-6--; --(CH.sub.2).sub.2--O--(CH.sub.2).sub.2--;
or --(CH.sub.2).sub.2--NR.sup.B--(CH.sub.2).sub.2--, wherein
R.sup.B means --H or --C.sub.1-C.sub.6-alkyl, linear or branched,
saturated or unsaturated, unsubstituted or substituted with one,
two, three or four substituents independently of one another
selected from the group consisting of --F, --Cl, --Br and --I; or a
physiologically acceptable salt thereof.
[0022] Preferably, aryl includes but is not limited to phenyl and
naphthyl. Preferably, heteroaryl includes but is not limited to
-1,2-benzodioxole, -pyrazinyl, -pyridazinyl, -pyridinyl,
-pyrimidinyl, -thienyl, -imidazolyl, -benzimidazolyl, -thiazolyl,
-1,3,4-thiadiazolyl, -benzothiazolyl, -oxazolyl, -benzoxazolyl,
-pyrazolyl, -quinolinyl, -isoquinolinyl, -quinazolinyl, -indolyl,
-indolinyl, -benzo[c][1,2,5]oxadiazolyl, -imidazo[1,2-a]pyrazinyl,
or -1H-pyrrolo[2,3-b]pyridinyl. Preferably, cycloalkyl includes but
is not limited to -cyclopropyl, -cyclobutyl, -cyclopentyl and
-cyclohexyl. Preferably, heterocycloalkyl includes but is not
limited to -aziridinyl, -azetidinyl, -pyrrolidinyl, -piperidinyl,
-piperazinyl, -morpholinyl, -sulfamorpholinyl, -oxiridinyl,
-oxetanyl, -tetrahydropyranyl, and -pyranyl.
[0023] When a moiety is connected through an asymmetric group such
as --C(.dbd.O)O-- or --C(.dbd.O)O--CH.sub.2--, said asymmetric
group may be arranged in either direction. For example, when
R.sup.4 is connected to the core structure through --C(.dbd.O)O--,
the arrangement may be either R.sup.4--C(.dbd.O)O-core or
core-C(.dbd.O)O--R.sup.4.
[0024] In preferred embodiments of the compound according to the
invention,
R.sup.7 and R.sup.8 independently of one another mean --H or
--C.sub.1-C.sub.6-alkyl; preferably --H or --CH.sub.3; or R.sup.7
and R.sup.8 together with the carbon atom to which they are
attached form a 3-12-membered cycloalkyl moiety, saturated or
unsaturated, unsubstituted, mono- or polysubstituted; preferably
cyclopropyl, cyclobutyl or cyclopentyl, in each case unsubstituted;
or a 3-12-membered heterocycloalkyl moiety, saturated or
unsaturated, unsubstituted, mono- or polysubstituted; preferably
oxetanly, tetrahydrofuranyl or tetrahydropyranyl, in each case
unsubstituted; and/or R.sup.9, R.sup.10, R.sup.11, R.sup.12,
R.sup.13, R.sup.14, R.sup.16, R.sup.17, R.sup.18, R.sup.19, and
R.sup.20 independently of one another mean --H, --F, --OH, or
--C.sub.1-C.sub.6-alkyl; preferably --H.
[0025] In a preferred embodiment of the compound according to the
invention, R.sup.1 means --H; and R.sup.2 means
--C.sub.1-C.sub.6-alkyl, linear or branched, saturated or
unsaturated, unsubstituted, mono- or polysubstituted. Preferably,
R.sup.1 means --H and R.sup.2 means --CH.sub.3.
[0026] In another preferred embodiment of the compound according to
the invention, R.sup.1 means --CH.sub.3; and R.sup.2 means
--C.sub.1-C.sub.6-alkyl, linear or branched, saturated or
unsaturated, unsubstituted, mono- or polysubstituted. Preferably,
R.sup.1 means --CH.sub.3 and R.sup.2 means --CH.sub.3.
[0027] In still another preferred embodiment of the compound
according to the invention, R.sup.1 and R.sup.2 together with the
nitrogen atom to which they are attached form a ring and mean
--(CH.sub.2).sub.3-6--. Preferably, R.sup.1 and R.sup.2 together
with the nitrogen atom to which they are attached form a ring and
mean --(CH.sub.2).sub.3--.
[0028] In yet another preferred embodiment, [0029] R.sup.1 means
--H or --CH.sub.3; and [0030] R.sup.2 means a 3-12-membered
cycloalkyl moiety, saturated or unsaturated, unsubstituted; wherein
said 3-12-membered cycloalkyl moiety is connected through
--CH.sub.2--, unsubstituted; preferably --CH.sub.2-cycloalkyl,
--CH.sub.2-cyclobutyl or --CH.sub.2-cyclopentyl; or R.sup.2 means a
3-12-membered heterocycloalkyl moiety, saturated or unsaturated,
unsubstituted; wherein said 3-12-membered heterocycloalkyl moiety
is connected through --CH.sub.2--, unsubstituted; preferably
--CH.sub.2-oxetanyl or --CH.sub.2-tetrahydrofuranyl.
[0031] In a preferred embodiment of the compound according to the
invention, R.sup.3 means --C.sub.1-C.sub.6-alkyl, linear or
branched, saturated or unsaturated, unsubstituted, mono- or
polysubstituted. Preferably, R.sup.3 means --C.sub.1-C.sub.6-alkyl,
linear or branched, saturated or unsaturated, unsubstituted or
monosubstituted with --OCH.sub.3.
[0032] In another preferred embodiment of the compound according to
the invention, R.sup.3 means a 6-14-membered aryl moiety,
unsubstituted, mono- or polysubstituted, optionally connected
through --C.sub.1-C.sub.6-alkylene-, linear or branched, saturated
or unsaturated, unsubstituted. In a preferred embodiment, R.sup.3
means -phenyl unsubstituted, mono- or polysubstituted. More
preferably, R.sup.3 means -phenyl unsubstituted, mono- or
disubstituted with --F, --Cl, --CH.sub.3, --CF.sub.3, --OH,
--OCH.sub.3, --OCF.sub.3 or --OCH.sub.2OCH.sub.3, preferably --F.
In another preferred embodiment, R.sup.3 means -benzyl
unsubstituted, mono- or polysubstituted. More preferably, R.sup.3
means -benzyl unsubstituted, mono- or disubstituted with --F, --Cl,
--CH.sub.3, --CF.sub.3, --OH, --OCH.sub.3, --OCF.sub.3 or
--OCH.sub.2OCH.sub.3, preferably --F.
[0033] In still another preferred embodiment of the compound
according to the invention, R.sup.3 means a 5-14-membered
heteroaryl moiety, unsubstituted, mono- or polysubstituted.
Preferably, R.sup.3 means -thienyl or -pyridinyl, in each case
unsubstituted, mono- or polysubstituted. More preferably, R.sup.3
means -thienyl, -pyridinyl, -imidazolyl or benzimidazolyl, in each
case unsubstituted or monosubstituted with --F, --Cl or
--CH.sub.3.
[0034] In a preferred embodiment of the compound according to the
invention, R.sup.4 means --H.
[0035] In another preferred embodiment of the compound according to
the invention, R.sup.4 means --C.sub.1-C.sub.6-alkyl, linear or
branched, saturated or unsaturated, unsubstituted, mono- or
polysubstituted. Preferably, R.sup.4 means --C.sub.1-C.sub.6-alkyl,
linear or branched, saturated or unsaturated, unsubstituted or
monosubstituted with a substituent selected from the group
consisting of --F, --Cl, --Br, --I, --CN, --CF.sub.3, --OH,
--O--C.sub.1-C.sub.4-alkyl, --OCF.sub.3,
--O--(CH.sub.2CH.sub.2--O).sub.1-30--H,
--O--(CH.sub.2CH.sub.2--O).sub.1-30--CH.sub.3,
--OC(.dbd.O)C.sub.1-C.sub.4-alkyl,
--C(.dbd.O)C.sub.1-C.sub.4-alkyl, --C(.dbd.O)OH,
--C(.dbd.O)OC.sub.1-C.sub.4-alkyl, --C(.dbd.O)NH.sub.2,
--C(.dbd.O)NHC.sub.1-C.sub.4-alkyl,
--C(.dbd.O)NHC.sub.1-C.sub.4-alkylene-CN,
--C(.dbd.O)NHC.sub.1-C.sub.4-alkylene-O--C.sub.1-C.sub.4-alkyl,
--C(.dbd.O)N(C.sub.1-C.sub.4-alkyl).sub.2;
--S(.dbd.O)C.sub.1-C.sub.4-alkyl, and
--S(.dbd.O).sub.2C.sub.1-C.sub.4-alkyl; or with
--C(.dbd.O)NR.sup.21R.sup.22 wherein R.sup.21 and R.sup.22 together
with the nitrogen atom to which they are attached form a ring and
mean --(CH.sub.2).sub.3-6--,
--(CH.sub.2).sub.2--O--(CH.sub.2).sub.2--, or
--(CH.sub.2).sub.2--NR.sup.B--(CH.sub.2).sub.2--, wherein R.sup.B
means --H or --C.sub.1-C.sub.6-alkyl; or with
--C(.dbd.O)NH-3-12-membered cycloalkyl, saturated or unsaturated,
unsubstituted or monosubstituted with --F, --Cl, --Br, --I, --CN,
or --OH; or with --C(.dbd.O)NH-3-12-membered heterocycloalkyl,
saturated or unsaturated, unsubstituted or monosubstituted with
--F, --Cl, --Br, --I, --CN, or --OH. More preferably, R.sup.4 means
--C.sub.1-C.sub.6-alkyl, linear or branched, saturated or
unsaturated, unsubstituted or monosubstituted with
--O--C.sub.1-C.sub.4-alkyl or
--C(.dbd.O)N(C.sub.1-C.sub.4-alkyl).sub.2.
[0036] In still another preferred embodiment of the compound
according to the invention, R.sup.4 means a 3-12-membered
cycloalkyl moiety, saturated or unsaturated, unsubstituted, mono-
or polysubstituted; wherein the 3-12-membered cycloalkyl moiety is
connected through --C.sub.1-C.sub.6-alkylene-, linear or branched,
saturated or unsaturated, unsubstituted, mono- or polysubstituted.
Preferably, R.sup.4 means a 3-12-membered cycloalkyl moiety,
saturated or unsaturated, unsubstituted, mono- or polysubstituted;
wherein said 3-12-membered cycloalkyl moiety is connected through
--CH.sub.2-- or --CH.sub.2CH.sub.2--. More preferably, R.sup.4
means a 3-12-membered cycloalkyl moiety, saturated or unsaturated,
unsubstituted or substituted with one, two, three or four
substituents independently of one another selected from the group
consisting of --F, --Cl, --Br, --I, --CN, --OH,
--C.sub.1-C.sub.4-alkyl, --O--C.sub.1-C.sub.4-alkyl, --C(.dbd.O)OH,
--C(.dbd.O)OC.sub.1-C.sub.4-alkyl, --C(.dbd.O)NH.sub.2,
--C(.dbd.O)NHC.sub.1-C.sub.4-alkyl,
--C(.dbd.O)N(C.sub.1-C.sub.4-alkyl).sub.2,
--S(.dbd.O)C.sub.1-C.sub.4-alkyl and
--S(.dbd.O).sub.2C.sub.1-C.sub.4-alkyl; wherein said 3-12-membered
cycloalkyl moiety is connected through --CH.sub.2-- or
--CH.sub.2CH.sub.2--.
[0037] In a preferred embodiment of the compound according to the
invention, R.sup.4 means a 3-12-membered heterocycloalkyl moiety,
saturated or unsaturated, unsubstituted, mono- or polysubstituted;
wherein said 3-12-membered heterocycloalkyl moiety is connected
through --C.sub.1-C.sub.6-alkylene-, linear or branched, saturated
or unsaturated, unsubstituted, mono- or polysubstituted.
Preferably, R.sup.4 means a 3-12-membered heterocycloalkyl moiety,
saturated or unsaturated, unsubstituted, mono- or polysubstituted;
wherein said 3-12-membered heterocycloalkyl moiety is connected
through --CH.sub.2-- or --CH.sub.2CH.sub.2--. More preferably,
R.sup.4 means -oxetanyl, -tetrahydrofuranyl or -tetrahydropyranyl,
in each case unsubstituted or substituted with one, two, three or
four substituents independently of one another selected from the
group consisting of --F, --Cl, --Br, --I, --CN, --OH,
--C.sub.1-C.sub.4-alkyl, --O--C.sub.1-C.sub.4-alkyl, --C(.dbd.O)OH,
--C(.dbd.O)OC.sub.1-C.sub.4-alkyl, --C(.dbd.O)NH.sub.2,
--C(.dbd.O)NHC.sub.1-C.sub.4-alkyl,
--C(.dbd.O)N(C.sub.1-C.sub.4-alkyl).sub.2,
--S(.dbd.O)C.sub.1-C.sub.4-alkyl and
--S(.dbd.O).sub.2C.sub.1-C.sub.4-alkyl; wherein said -oxetanyl,
-tetrahydrofuranyl or -tetrahydropyranyl is connected through
--CH.sub.2-- or --CH.sub.2CH.sub.2--.
[0038] In yet another preferred embodiment of the compound
according to the invention, R.sup.4 means a 6-14-membered aryl
moiety, unsubstituted, mono- or polysubstituted; wherein said
6-14-membered aryl moiety is connected through
--C.sub.1-C.sub.6-alkylene-, linear or branched, saturated or
unsaturated, unsubstituted, mono- or polysubstituted. Preferably,
R.sup.4 means -phenyl, unsubstituted, mono- or polysubstituted;
wherein said -phenyl is connected through --CH.sub.2-- or
--CH.sub.2CH.sub.2--. More preferably, R.sup.4 means -phenyl,
unsubstituted or substituted with one, two, three or four
substituents independently of one another selected from the group
consisting of --F, --Cl, --Br, --I, --CN, --OH,
--C.sub.1-C.sub.4-alkyl, --O--C.sub.1-C.sub.4-alkyl, --C(.dbd.O)OH,
--C(.dbd.O)OC.sub.1-C.sub.4-alkyl, --C(.dbd.O)NH.sub.2,
--C(.dbd.O)NHC.sub.1-C.sub.4-alkyl,
--C(.dbd.O)N(C.sub.1-C.sub.4-alkyl).sub.2,
--S(.dbd.O)C.sub.1-C.sub.4-alkyl and
--S(.dbd.O).sub.2C.sub.1-C.sub.4-alkyl; wherein said -phenyl is
connected through --CH.sub.2-- or --CH.sub.2CH.sub.2--.
[0039] In a further preferred embodiment of the compound according
to the invention, R.sup.4 means a 5-14-membered heteroaryl moiety,
unsubstituted, mono- or polysubstituted; wherein said 5-14-membered
heteroaryl moiety is connected through --C.sub.1-C.sub.6-alkylene-,
linear or branched, saturated or unsaturated, unsubstituted, mono-
or polysubstituted. Preferably, R.sup.4 means a 5-14-membered
heteroaryl moiety, unsubstituted, mono- or polysubstituted; wherein
said -phenyl is connected through --CH.sub.2-- or
--CH.sub.2CH.sub.2--. More preferably, R.sup.4 means -pyridinyl,
-pyrimidinyl, -pyrazinyl, or -pyrazolinyl, in each case
unsubstituted or substituted with one, two, three or four
substituents independently of one another selected from the group
consisting of --F, --Cl, --Br, --I, --CN, --OH,
--C.sub.1-C.sub.4-alkyl, --O--C.sub.1-C.sub.4-alkyl, --C(.dbd.O)OH,
--C(.dbd.O)OC.sub.1-C.sub.4-alkyl, --C(.dbd.O)NH.sub.2,
--C(.dbd.O)NHC.sub.1-C.sub.4-alkyl,
--C(.dbd.O)N(C.sub.1-C.sub.4-alkyl).sub.2,
--S(.dbd.O)C.sub.1-C.sub.4-alkyl and
--S(.dbd.O).sub.2C.sub.1-C.sub.4-alkyl; wherein said -pyridinyl,
-pyrimidinyl, -pyrazinyl, or -pyrazolinyl is connected through
--CH.sub.2-- or --CH.sub.2CH.sub.2--.
[0040] In a preferred embodiment of the compound according to the
invention, R.sup.5 means --H.
[0041] In another preferred embodiment of the compound according to
the invention, R.sup.5 means --C.sub.1-C.sub.6-alkyl, linear or
branched, saturated or unsaturated, unsubstituted, mono- or
polysubstituted. Preferably, R.sup.5 means --C.sub.1-C.sub.6-alkyl,
linear or branched, saturated, unsubstituted, mono- or
polysubstituted. More preferably, R.sup.5 means
--C.sub.1-C.sub.6-alkyl, linear or branched, saturated,
unsubstituted or monosubstituted with a substituent selected from
the group consisting of --F, --Cl, --Br, --I, --CN, --OH,
--O--C.sub.1-C.sub.4-alkyl, --C(.dbd.O)OH,
--C(.dbd.O)OC.sub.1-C.sub.4-alkyl, --C(.dbd.O)NH.sub.2,
--C(.dbd.O)NHC.sub.1-C.sub.4-alkyl,
--C(.dbd.O)N(C.sub.1-C.sub.4-alkyl).sub.2,
--S(.dbd.O)C.sub.1-C.sub.4-alkyl and
--S(.dbd.O).sub.2C.sub.1-C.sub.4-alkyl.
[0042] In still another preferred embodiment of the compound
according to the invention, R.sup.5 means a 3-12-membered
cycloalkyl moiety, saturated or unsaturated, unsubstituted, mono-
or polysubstituted, wherein said 3-12-membered cycloalkyl moiety is
optionally connected through --C.sub.1-C.sub.6-alkylene-, linear or
branched, saturated or unsaturated, unsubstituted, mono- or
polysubstituted; preferably through --CH.sub.2-- or
--CH.sub.2CH.sub.2--. Preferably, R.sup.5 means a 3-6-membered
cycloalkyl moiety, saturated, unsubstituted, mono- or
polysubstituted, wherein said 3-12-membered cycloalkyl moiety is
connected through --C.sub.1-C.sub.6-alkylene-, linear or branched,
saturated, unsubstituted. More preferably, R.sup.5 means
-cyclobutyl, unsubstituted or monosubstituted with --F, --OH, --CN
or --C.sub.1-C.sub.4-alkyl, wherein said -cyclobutyl is connected
through --CH.sub.2-- or --CH.sub.2CH.sub.2--.
[0043] In yet another preferred embodiment of the compound
according to the invention, R.sup.5 means a 3-12-membered
heterocycloalkyl moiety, saturated or unsaturated, unsubstituted,
mono- or polysubstituted; wherein said 3-12-membered
heterocycloalkyl moiety is optionally connected through
--C.sub.1-C.sub.6-alkylene-, linear or branched, saturated or
unsaturated, unsubstituted, mono- or polysubstituted. Preferably,
R.sup.5 means a 4-6-membered heterocycloalkyl moiety, saturated or
unsaturated, unsubstituted, mono- or polysubstituted. More
preferably, R.sup.5 means -heterocyclobutyl, unsubstituted.
[0044] In a further preferred embodiment of the compound according
to the invention, R.sup.5 means a 5-14-membered heteroaryl moiety,
unsubstituted, mono- or polysubstituted; wherein said 5-14-membered
heteroaryl moiety is optionally connected through
--C.sub.1-C.sub.6-alkylene-, linear or branched, saturated or
unsaturated, unsubstituted, mono- or polysubstituted. Preferably,
R.sup.5 means a 5-6-membered heteroaryl moiety, unsubstituted,
mono- or polysubstituted, wherein said 5-6-membered heteroaryl
moiety is optionally connected through --CH.sub.2--. More
preferably, R.sup.5 means a 5-6-membered heteroaryl moiety,
unsubstituted or substituted with one, two, three or four
substituents independently of one another selected from the group
consisting of --F, --Cl, --Br, --I, --CN, --OH,
--C.sub.1-C.sub.4-alkyl, --O--C.sub.1-C.sub.4-alkyl, --C(.dbd.O)OH,
--C(.dbd.O)OC.sub.1-C.sub.4-alkyl, --C(.dbd.O)NH.sub.2,
--C(.dbd.O)NHC.sub.1-C.sub.4-alkyl,
--C(.dbd.O)N(C.sub.1-C.sub.4-alkyl).sub.2,
--S(.dbd.O)C.sub.1-C.sub.4-alkyl and
--S(.dbd.O).sub.2C.sub.1-C.sub.4-alkyl, wherein said 5-6-membered
heteroaryl moiety is optionally connected through --CH.sub.2--.
Still more preferably, R.sup.5 means -oxazolyl, -pyridinyl,
-pyridazinyl or -pyrimidinyl, in each case unsubstituted or
substituted with one, two, three or four substituents independently
of one another selected from the group consisting of --F, --Cl, Br,
--I, --CN, --OH, --C.sub.1-C.sub.4-alkyl,
--O--C.sub.1-C.sub.4-alkyl, --C(.dbd.O)OH,
--C(.dbd.O)OC.sub.1-C.sub.4-alkyl, --C(.dbd.O)NH.sub.2,
--C(.dbd.O)NHC.sub.1-C.sub.4-alkyl,
--C(.dbd.O)N(C.sub.1-C.sub.4-alkyl).sub.2,
S(.dbd.O)C.sub.1-C.sub.4-alkyl and
--S(.dbd.O).sub.2C.sub.1-C.sub.4-alkyl, wherein said -oxazolyl,
-pyridinyl, -pyridazinyl or -pyrimidinyl is optionally connected
through --CH.sub.2--.
[0045] In a preferred embodiment of the compound according to the
invention, X means NR.sup.6 and R.sup.5 and R.sup.6 together with
the nitrogen atom to which they are attached form a 3-12-membered
heterocycloalkyl moiety, saturated or unsaturated, unsubstituted,
mono- or polysubstituted. Preferably, X means NR.sup.6 and R.sup.5
and R.sup.6 together with the nitrogen atom to which they are
attached form a 5-6-membered heterocycloalkyl moiety, saturated or
unsaturated, unsubstituted, mono- or polysubstituted. More
preferably, X means NR.sup.6 and R.sup.5 and R.sup.6 together with
the nitrogen atom to which they are attached form -pyrrolidinyl,
-pyrimidinyl, -morpholinyl, -thiomorpholinyl, -thiomorpholinyl
dioxide, or -piperazinyl, in each case unsubstituted or substituted
with one, two, three or four substituents independently of one
another selected from the group consisting of .dbd.O, --OH, and
--C(.dbd.O)NH.sub.2, wherein said -pyrrolidinyl, -pyrimidinyl,
-morpholinyl, -thiomorpholinyl, -thiomorpholinyl dioxide, or
-piperazinyl is optionally condensed with an imidazole moiety,
unsubstituted.
[0046] In a preferred embodiment of the compound according to the
invention, R.sup.5 means
--H;
[0047] --C.sub.1-C.sub.6-alkyl, linear or branched, saturated or
unsaturated, unsubstituted or substituted with one, two, three or
four substituents independently of one another selected from the
group consisting of --F, --Cl, --Br, --I, --CN,
--O--C.sub.1-C.sub.4-alkyl, --C(.dbd.O)OH,
--C(.dbd.O)OC.sub.1-C.sub.4-alkyl, --C(.dbd.O)NH.sub.2,
--C(.dbd.O)NHC.sub.1-C.sub.4-alkyl,
--C(.dbd.O)N(C.sub.1-C.sub.4-alkyl).sub.2, --OH,
--S(.dbd.O)C.sub.1-C.sub.4-alkyl and --S(.dbd.O).sub.2
C.sub.1-C.sub.4-alkyl; -cyclobutyl, unsubstituted or
monosubstituted with --OH; wherein said -cyclobutyl is connected
through --CH.sub.2--; -heterocyclobutyl, unsubstituted; or
-oxazolyl, -pyridinyl, -pyridazinyl or -pyrimidinyl, in each case
unsubstituted or substituted with one, two, three or four
substituents independently of one another selected from the group
consisting of --F, --Cl, Br, --I, --OH, --O--C.sub.1-C.sub.4-alkyl,
--CN, and --S(.dbd.O).sub.2C.sub.1-C.sub.4-alkyl; wherein said
-oxazolyl, -pyridinyl, -pyridazinyl or -pyrimidinyl is optionally
connected through --CH.sub.2--; in case X means NR.sup.6, R.sup.6
means --H or --CH.sub.3; or in case X means NR.sup.6, R.sup.5 and
R.sup.6 together with the nitrogen atom to which they are attached
form a piperidine moiety, a pyrrolidine moiety, a morpholine
moiety, a thiomorpholine moiety, a thiomorpholine dioxide moiety,
or a piperazine moiety, in each case unsubstituted or substituted
with one, two, three or four substituents independently of one
another selected from the group consisting of .dbd.O, --OH, and
--C(.dbd.O)NH.sub.2; wherein said piperidine moiety, pyrrolidine
moiety, morpholine moiety, thiomorpholine moiety, thiomorpholine
dioxide moiety, or piperazine moiety is optionally condensed with
an imidazole moiety, unsubstituted.
[0048] In a preferred embodiment of the compound according to the
invention, X means NR.sup.6 and R.sup.6 means --H or
--C.sub.1-C.sub.6-alkyl, linear or branched, saturated or
unsaturated, unsubstituted, mono- or polysubstituted. Preferably,
R.sup.6 means --H or --CH.sub.3. More preferably, R.sup.6 means
--H.
[0049] In preferred embodiments the compound according to the
invention has a structure according to any of general formulas
(II-A) to (VIII-C):
##STR00002## ##STR00003## ##STR00004## ##STR00005##
wherein in each case R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5,
R.sup.6, R.sup.7, R.sup.8, and X are defined as above, R.sup.C
means --H, --OH, --F, --CN or --C.sub.1-C.sub.4-alkyl; preferably
--H or --OH; R.sup.D means --H or --F; or a physiologically
acceptable salt thereof.
[0050] Preferably, the substructure of the compounds according to
general formula (I) represented by --C(.dbd.O)--X--R.sup.5
(R.sup.5, X, R.sup.7, R.sup.8, R.sup.9 and R.sup.10), i.e.
##STR00006##
or the corresponding substructure of any of above general formulas
(II-A) to (VIII-C) has preferably a meaning selected from the group
consisting of:
##STR00007## ##STR00008## ##STR00009## ##STR00010##
[0051] In particularly preferred embodiments of the compound
according to the invention,
R.sup.1 means --H or --CH.sub.3; and/or R.sup.2 means
--C.sub.1-C.sub.6-alkyl, linear or branched, saturated,
unsubstituted; preferably, R.sup.2 means --CH.sub.3 or
--CH.sub.2CH.sub.3; more preferably, R.sup.1 and R.sup.2 both mean
--CH.sub.3; and/or R.sup.3 means -phenyl, -thienyl or -pyridinyl,
in each case unsubstituted or substituted with one, two, three or
four substituents independently of one another selected from the
group consisting of --F, --Cl, --CN, --CH.sub.3,
--CH.sub.2CH.sub.3, --CH.sub.2F, --CHF.sub.2, --CF.sub.3,
--OCF.sub.3, --OH, --OCH.sub.3, --C(.dbd.O)NH.sub.2,
C(.dbd.O)NHCH.sub.3, --C(.dbd.O)N(CH.sub.3).sub.2, --NH.sub.2,
--NHCH.sub.3, --N(CH.sub.3).sub.2, --NHC(.dbd.O)CH.sub.3,
--CH.sub.2OH, --SOCH.sub.3 and --SO.sub.2CH.sub.3; preferably,
R.sup.3 means -phenyl, -thienyl or -pyridinyl, in each case
unsubstituted or substituted with --F; more preferably, R.sup.3
means phenyl, unsubstituted or monosubstituted with --F; and/or
R.sup.4 means
--H;
[0052] --C.sub.1-C.sub.6-alkyl, linear or branched, saturated,
unsubstituted or substituted with one, two, three or four
substituents independently of one another selected from the group
consisting of --F, --Cl, --Br, --I, --CN, --OH, and
--O--C.sub.1-C.sub.4-alkyl; 3-6-membered cycloalkyl, unsubstituted
or substituted with one, two, three or four substituents
independently of one another selected from the group consisting of
--F, --Cl, --Br, --I, --CN, --OH, and --O--C.sub.1-C.sub.4-alkyl,
wherein said 3-6-membered cycloalkyl is connected through
--C.sub.1-C.sub.6-alkylene; preferably, R.sup.4 means 3-6-membered
cycloalkyl, unsubstituted or substituted with one, two, three or
four substituents independently of one another selected from the
group consisting of --F, --Cl, --Br, --I, --CN, --OH, and
--O--C.sub.1-C.sub.4-alkyl, wherein said 3-6-membered cycloalkyl is
connected through --CH.sub.2-- or --CH.sub.2CH.sub.2--; more
preferably, R.sup.4 means -cyclopropyl or -cyclobutyl,
unsubstituted or monosubstituted with --OH, wherein said
-cyclopropyl or -cyclobutyl is connected through --CH.sub.2--; or
3-6-membered heterocycloalkyl, unsubstituted or substituted with
one, two, three or four substituents independently of one another
selected from the group consisting of --F, --Cl, --Br, --I, --CN,
--OH, and --O--C.sub.1-C.sub.4-alkyl, wherein said 3-6-membered
heterocycloalkyl is connected through --C.sub.1-C.sub.6-alkylene;
and/or X means --O-- or --NR.sup.6--; and/or R.sup.5 means
--H;
[0053] --C.sub.1-C.sub.6-alkyl, linear or branched, saturated or
unsaturated, unsubstituted or substituted with one, two, three or
four substituents independently of one another selected from the
group consisting of --F, --Cl, --Br, --I, --CN,
--O--C.sub.1-C.sub.4-alkyl, --C(.dbd.O)OH,
--C(.dbd.O)OC.sub.1-C.sub.4-alkyl, --C(.dbd.O)NH.sub.2,
--C(.dbd.O)NHC.sub.1-C.sub.4-alkyl,
--C(.dbd.O)N(C.sub.1-C.sub.4-alkyl).sub.2, --OH,
--S(.dbd.O)C.sub.1-C.sub.4-alkyl and --S(.dbd.O).sub.2
C.sub.1-C.sub.4-alkyl; -cyclobutyl, unsubstituted or
monosubstituted with --OH; wherein said -cyclobutyl is connected
through --CH.sub.2--; -heterocyclobutyl, unsubstituted; or
-oxazolyl, -pyridinyl, -pyridazinyl or -pyrimidinyl, in each case
unsubstituted or substituted with one, two, three or four
substituents independently of one another selected from the group
consisting of --F, --Cl, Br, --I, --OH, --O--C.sub.1-C.sub.4-alkyl,
--CN, and --S(.dbd.O).sub.2C.sub.1-C.sub.4-alkyl; wherein said
-oxazolyl, -pyridinyl, -pyridazinyl or -pyrimidinyl is optionally
connected through --CH.sub.2--; preferably pyridinyl or
pyridazinyl, in each case unsubstituted; and/or in case X means
NR.sup.6, R.sup.6 means --H or --CH.sub.3, preferably --H; or in
case X means NR.sup.6, R.sup.5 and R.sup.6 together with the
nitrogen atom to which they are attached form a piperidine moiety,
a pyrrolidine moiety, a morpholine moiety, a thiomorpholine moiety,
a thiomorpholine dioxide moiety, or a piperazine moiety, in each
case unsubstituted or substituted with one, two, three or four
substituents independently of one another selected from the group
consisting of .dbd.O, --OH, and --C(.dbd.O)NH.sub.2; wherein said
piperidine moiety, pyrrolidine moiety, morpholine moiety,
thiomorpholine moiety, thiomorpholine dioxide moiety, or piperazine
moiety is optionally condensed with an imidazole moiety,
unsubstituted; and/or R.sup.7 and R.sup.8 independently of one
another mean --H or --CH.sub.3; or R.sup.7 and R.sup.8 together
with the carbon atom to which they are attached form a ring
selected from the group consisting of cyclopropyl, cyclobutyl,
heterocyclobutyl and heterocyclohexyl, in each case unsubstituted;
and/or R.sup.9, R.sup.10, R.sup.11, R.sup.12, R.sup.13, R.sup.14,
R.sup.15, R.sup.16, R.sup.17, R.sup.18, R.sup.19, and R.sup.20 mean
--H.
[0054] In particularly preferred embodiments of the compound
according to the invention,
R.sup.1 means --H or --CH.sub.3; and/or R.sup.2 means
--C.sub.1-C.sub.6-alkyl, linear or branched, saturated,
unsubstituted; preferably, R.sup.2 means --CH.sub.3 or
--CH.sub.2CH.sub.3; more preferably, R.sup.1 and R.sup.2 both mean
--CH.sub.3; and/or R.sup.3 means -phenyl, -thienyl or -pyridinyl,
in each case unsubstituted or substituted with one, two, three or
four substituents independently of one another selected from the
group consisting of --F, --Cl, --CN, --CH.sub.3,
--CH.sub.2CH.sub.3, --CH.sub.2F, --CHF.sub.2, --CF.sub.3,
--OCF.sub.3, --OH, --OCH.sub.3, --C(.dbd.O)NH.sub.2,
C(.dbd.O)NHCH.sub.3, --C(.dbd.O)N(CH.sub.3).sub.2, --NH.sub.2,
--NHCH.sub.3, --N(CH.sub.3).sub.2, --NHC(.dbd.O)CH.sub.3,
--CH.sub.2OH, SOCH.sub.3 and SO.sub.2CH.sub.3; preferably, R.sup.3
means -phenyl, -thienyl or -pyridinyl, in each case unsubstituted
or substituted with --F; more preferably, R.sup.3 means phenyl,
unsubstituted; and/or R.sup.4 means
--H;
[0055] --C.sub.1-C.sub.6-alkyl, linear or branched, saturated,
unsubstituted or substituted with one, two, three or four
substituents independently of one another selected from the group
consisting of --F, --Cl, --Br, --I, --CN, --OH, and
--O--C.sub.1-C.sub.4-alkyl; or 3-6-membered cycloalkyl,
unsubstituted or substituted with one, two, three or four
substituents independently of one another selected from the group
consisting of --F, --Cl, --Br, --I, --CN, --OH, and
--O--C.sub.1-C.sub.4-alkyl, wherein said 3-6-membered cycloalkyl is
connected through --C.sub.1-C.sub.6-alkylene; preferably, R.sup.4
means 3-6-membered cycloalkyl, unsubstituted or substituted with
one, two, three or four substituents independently of one another
selected from the group consisting of --F, --Cl, --Br, --I, --CN,
--OH, and --O--C.sub.1-C.sub.4-alkyl, wherein said 3-6-membered
cycloalkyl is connected through --CH.sub.2-- or
--CH.sub.2CH.sub.2--; more preferably, R.sup.4 means -cyclobutyl,
unsubstituted or monosubstituted with --OH, wherein said
-cyclobutyl is connected through --CH.sub.2--; and/or X means --O--
or --NR.sup.6--; and/or R.sup.5 means
--H;
[0056] --C.sub.1-C.sub.6-alkyl, linear or branched, saturated or
unsaturated, unsubstituted or substituted with one, two, three or
four substituents independently of one another selected from the
group consisting of --F, --Cl, --Br, --I, --CN,
--O--C.sub.1-C.sub.4-alkyl, --C(.dbd.O)OH,
--C(.dbd.O)OC.sub.1-C.sub.4-alkyl, --C(.dbd.O)NH.sub.2,
--C(.dbd.O)NHC.sub.1-C.sub.4-alkyl,
--C(.dbd.O)N(C.sub.1-C.sub.4-alkyl).sub.2, --OH,
--S(.dbd.O)C.sub.1-C.sub.4-alkyl and --S(.dbd.O).sub.2
C.sub.1-C.sub.4-alkyl; -cyclobutyl, unsubstituted or
monosubstituted with --OH; wherein said -cyclobutyl is connected
through --CH.sub.2--; -heterocyclobutyl, unsubstituted; or
-oxazolyl, -pyridinyl, -pyridazinyl or -pyrimidinyl, in each case
unsubstituted or substituted with one, two, three or four
substituents independently of one another selected from the group
consisting of --F, --Cl, Br, --I, --OH, --O--C.sub.1-C.sub.4-alkyl,
--CN, and --S(.dbd.O).sub.2C.sub.1-C.sub.4-alkyl; wherein said
-oxazolyl, -pyridinyl, -pyridazinyl or -pyrimidinyl is optionally
connected through --CH.sub.2--; preferably pyridinyl or
pyridazinyl, in each case unsubstituted; and/or in case X means
NR.sup.6, R.sup.6 means --H or --CH.sub.3, preferably R.sup.6 means
--H; and/or or in case X means NR.sup.6, R.sup.5 and R.sup.6
together with the nitrogen atom to which they are attached form a
piperidine moiety, a pyrrolidine moiety, a morpholine moiety, a
thiomorpholine moiety, a thiomorpholine dioxide moiety, or a
piperazine moiety, in each case unsubstituted or substituted with
one, two, three or four substituents independently of one another
selected from the group consisting of .dbd.O, --OH, and
--C(.dbd.O)NH.sub.2; wherein said piperidine moiety, pyrrolidine
moiety, morpholine moiety, thiomorpholine moiety, thiomorpholine
dioxide moiety, or piperazine moiety is optionally condensed with
an imidazole moiety, unsubstituted; and/or R.sup.7 and R.sup.8
independently of one another mean --H or --CH.sub.3; and/or
R.sup.9, R.sup.10, R.sup.11, R.sup.12, R.sup.13, R.sup.14,
R.sup.15, R.sup.16, R.sup.17, R.sup.18, R.sup.19, and R.sup.20 mean
--H.
[0057] Preferably, the compound according to the invention is
selected from the group consisting of
TABLE-US-00001 SC_5001
CIS-3-[8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-2-oxo-8--
phenyl-1,3-
diazaspiro[4.5]decan-3-yl]-N-pyridazin-3-yl-propionamide SC_5002
CIS-3-[8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-2-oxo-8-p-
henyl-1,3- diazaspiro[4.5]decan-3-yl]-propionamide SC_5003
CIS-3-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-
diazaspiro[4.5]decan-3-yl]-N-(2-methoxy-pyridin-4-yl)-propionamide
SC_5004
CIS-3-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-
diazaspiro[4.5]decan-3-yl]-N-(6-methoxy-pyridin-3-yl)-propionamide
SC_5005
CIS-3-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-
diazaspiro[4.5]decan-3-yl]-N-(3-methoxy-pyridin-4-yl)-propionamide
SC_5006
CIS-3-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-
diazaspiro[4.5]decan-3-yl]-N-(6-methoxy-pyridazin-3-yl)-propionamide
SC_5007
CIS-3-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-
diazaspiro[4.5]decan-3-yl]-N-(5-methylsulfonyl-pyridin-2-yl)-propionamide
SC_5008
CIS-3-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-
diazaspiro[4.5]decan-3-yl]-N-(5-methoxy-pyridin-2-yl)-propionamide
SC_5009
CIS-3-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-
diazaspiro[4.5]decan-3-yl]-N-(6-methylsulfonyl-pyridin-3-yl)-propionamide
SC_5010
CIS-3-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-
diazaspiro[4.5]decan-3-yl]-N-(6-methoxy-pyrazin-2-yl)-propionamide
SC_5011
CIS-3-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-
diazaspiro[4.5]decan-3-yl]-N-(4-methoxy-pyridin-2-yl)-propionamide
SC_5012
CIS-3-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-
diazaspiro[4.5]decan-3-yl]-N-(oxazol-5-yl-methyl)-propionamide
SC_5013
CIS-3-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-
diazaspiro[4.5]decan-3-yl]-N-(oxazol-2-yl-methyl)-propionamide
SC_5014
CIS-1-(Cyclobutyl-methyl)-3-[3-[3,4-dihydroxy-piperidin-1-yl]-3-ox-
o-propyl]-8- dimethylamino-8-phenyl-1,3-diazaspiro[4.5]decan-2-one
SC_5015
CIS-1-(Cyclobutyl-methyl)-3-[3-[3,4-dihydroxy-pyrrolidin-1-yl]-3-o-
xo-propyl]-8- dimethylamino-8-phenyl-1,3-diazaspiro[4.5]decan-2-one
SC_5016
CIS-1-(Cyclobutyl-methyl)-3-[3-[(3S,4R)-3,4-dihydroxy-pyrrolidin-1-
-yl]-3-oxo-propyl]-
8-dimethylamino-8-phenyl-1,3-diazaspiro[4.5]decan-2-one SC_5017
CIS-1-(Cyclobutyl-methyl)-8-dimethylamino-3-[3-(3-hydroxy-piperidi-
n-1-yl)-3-oxo- propyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one
SC_5018
CIS-3-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-
diazaspiro[4.5]decan-3-yl]-N-[(1-hydroxy-cyclobutyl)-methyl]-propionamide
SC_5019
CIS-1-(Cyclobutyl-methyl)-8-dimethylamino-3-[3-oxo-3-(5,6,7,8-tetr-
ahydro-
[1,2,4]triazolo[1,5-a]pyrazin-7-yl)-propyl]-8-phenyl-1,3-diazaspiro[4.5]d-
ecan-2-one SC_5020
CIS-3-[3-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-
-
diazaspiro[4.5]decan-3-yl]-propanoylamino]-N,N-dimethyl-propionamide
SC_5022
CIS-N-(2-Cyano-pyrimidin-5-yl)-3-[8-dimethylamino-1-[(1-hydroxy-cy-
clobutyl)-
methyl]-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-propionamide
SC_5023
CIS-3-[8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-2-oxo-8-p-
henyl-1,3- diazaspiro[4.5]decan-3-yl]-N-pyrimidin-2-yl-propionamide
SC_5024
CIS-3-[8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-2-oxo-8-p-
henyl-1,3-
diazaspiro[4.5]decan-3-yl]-N-(4-hydroxy-pyrimidin-2-yl)-propionamide
SC_5025
CIS-3-[8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-2-oxo-8-p-
henyl-1,3-
diazaspiro[4.5]decan-3-yl]-N-(4-methoxy-pyrimidin-2-yl)-propionamide
SC_5026
CIS-3-[1-(Cyclobutyl-methyl)-8-methylamino-2-oxo-8-phenyl-1,3-diaz-
aspiro[4.5]decan- 3-yl]-2,2-dimethyl-propionamide SC_5027
CIS-3-[1-[(1-Hydroxy-cyclobutyl)-methyl]-8-methylamino-2-oxo-8-phe-
nyl-1,3-
diazaspiro[4.5]decan-3-yl]-N-(2-hydroxy-ethyl)-propionamide SC_5028
CIS-3-[1-[(1-Hydroxy-cyclobutyl)-methyl]-8-methylamino-2-oxo-8-phe-
nyl-1,3- diazaspiro[4.5]decan-3-yl]-propionamide SC_5029
CIS-3-[1-[(1-Hydroxy-cyclobutyl)-methyl]-8-methylamino-2-oxo-8-phe-
nyl-1,3- diazaspiro[4.5]decan-3-yl]-N-methyl-propionamide SC_5030
CIS-3-[1-[(1-Hydroxy-cyclobutyl)-methyl]-8-methylamino-2-oxo-8-phe-
nyl-1,3- diazaspiro[4.5]decan-3-yl]-N-pyridazin-3-yl-propionamide
SC_5031
CIS-3-[8-Dimethylamino-1-(2-methoxy-ethyl)-2-oxo-8-phenyl-1,3-
diazaspiro[4.5]decan-3-yl]-N-(2-hydroxy-ethyl)-propionamide SC_5032
CIS-3-[8-Dimethylamino-1-(2-methoxy-ethyl)-2-oxo-8-phenyl-1,3-
diazaspiro[4.5]decan-3-yl]-N-methyl-propionamide SC_5033
CIS-3-[8-Dimethylamino-1-(2-methoxy-ethyl)-2-oxo-8-phenyl-1,3-
diazaspiro[4.5]decan-3-yl]-N-pyrimidin-5-yl-propionamide SC_5034
CIS-3-[8-Dimethylamino-1-(3-methoxy-propyl)-2-oxo-8-phenyl-1,3-
diazaspiro[4.5]decan-3-yl]-2,2-dimethyl-propionamide SC_5035
CIS-3-[8-Dimethylamino-1-(2-methoxy-ethyl)-2-oxo-8-phenyl-1,3-
diazaspiro[4.5]decan-3-yl]-2,2-dimethyl-propionamide SC_5036
CIS-3-[8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-2-oxo-8-p-
henyl-1,3- diazaspiro[4.5]decan-3-yl]-N-pyridin-3-yl-propionamide
SC_5037
CIS-3-[8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-2-oxo-8-p-
henyl-1,3- diazaspiro[4.5]decan-3-yl]-N-pyridin-4-yl-propionamide
SC_5038
CIS-2-[3-[8-Dimethylamino-1-(3-methoxy-propyl)-2-oxo-8-phenyl-1,3-
diazaspiro[4.5]decan-3-yl]-propanoylamino]-2-methyl-propionamide
SC_5039
CIS-3-[8-Dimethylamino-1-(3-methoxy-propyl)-2-oxo-8-phenyl-1,3-
diazaspiro[4.5]decan-3-yl]-N-(2-methylsulfonyl-ethyl)-propionamide
SC_5040
CIS-3-[8-Dimethylamino-1-(3-methoxy-propyl)-2-oxo-8-phenyl-1,3-
diazaspiro[4.5]decan-3-yl]-N-(2-hydroxy-ethyl)-propionamide SC_5041
CIS-8-Dimethylamino-1-(3-methoxy-propyl)-3-[3-oxo-3-(3-oxo-piperaz-
in-1-yl)-propyl]- 8-phenyl-1,3-diazaspiro[4.5]decan-2-one SC_5042
CIS-(2R)-1-[3-[8-Dimethylamino-1-(3-methoxy-propyl)-2-oxo-8-phenyl-
-1,3-
diazaspiro[4.5]decan-3-yl]-propanoyl]-pyrrolidine-2-carboxylic acid
amide SC_5043
CIS-N-(Carbamoyl-methyl)-3-[8-dimethylamino-1-(3-methoxy-propyl)-2-
-oxo-8-phenyl- 1,3-diazaspiro[4.5]decan-3-yl]-propionamide SC_5044
CIS-3-[8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-2-oxo-8-p-
henyl-1,3- diazaspiro[4.5]decan-3-yl]-N-pyridin-2-yl-propionamide
SC_5045
CIS-3-[1-(Cyclobutyl-methyl)-8-(ethyl-methyl-amino)-2-oxo-8-phenyl-
-1,3- diazaspiro[4.5]decan-3-yl]-2,2-dimethyl-propionamide SC_5046
CIS-3-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-
diazaspiro[4.5]decan-3-yl]-2,2-dimethyl-propionamide SC_5047
CIS-3-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-
diazaspiro[4.5]decan-3-yl]-propionamide SC_5048
CIS-3-[1-(Cyclobutyl-methyl)-8-[methyl-(2-methyl-propyl)-amino]-2--
oxo-8-phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N-methyl-propionamide
SC_5049
CIS-3-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-
diazaspiro[4.5]decan-3-yl]-N-methyl-propionamide SC_5051
CIS-3-[8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-2-oxo-8-p-
henyl-1,3-
diazaspiro[4.5]clecan-3-yl]-N-pyrimidin-5-yl-propionamide SC_5052
CIS-3-[8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-2-oxo-8-p-
henyl-1,3- diazaspiro[4.5]decan-3-yl]-N-methyl-propionamide SC_5053
CIS-3-[8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-2-oxo-8-p-
henyl-1,3-
diazaspiro[4.5]decan-3-yl]-N-(2-methoxy-ethyl)-propionamide SC_5054
CIS-3-[8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-2-oxo-8-p-
henyl-1,3-
diazaspiro[4.5]decan-3-yl]-N-(2-hydroxy-ethyl)-propionamide SC_5055
CIS-3-[8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-2-oxo-8-p-
henyl-1,3- diazaspiro[4.5]decan-3-yl]-N-(oxetan-3-yl)-propionamide
SC_5056
CIS-N-(Carbamoyl-methyl)-3-[1-(cyclobutyl-methyl)-8-dimethyl-amino-
-2-oxo-8-
phenyl-1,3-diazaspiro[4.5]decan-3-yl]-2,2-dimethyl-propionamide
SC_5057
CIS-N-(Carbamoyl-methyl)-3-[1-(cyclobutyl-methyl)-8-methylamino-2--
oxo-8-phenyl-
1,3-diazaspiro[4.5]decan-3-yl]-2,2-dimethyl-propionamide SC_5058
CIS-3-[8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-2-oxo-8-p-
henyl-1,3- diazaspiro[4.5]decan-3-yl]-2,2-dimethyl-propionamide
SC_5059
CIS-3-[1-[(1-Hydroxy-cyclobutyl)-methyl]-8-methylamino-2-oxo-8-phe-
nyl-1,3- diazaspiro[4.5]decan-3-yl]-N-(oxetan-3-yl)-propionamide
SC_5060
CIS-3-[1-[(1-Hydroxy-cyclobutyl)-methyl]-8-methylamino-2-oxo-8-phe-
nyl-1,3- diazaspiro[4.5]decan-3-yl]-2,2-dimethyl-propionamide
SC_5064
CIS-3-[8-(Ethyl-methyl-amino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]de-
can-3-yl]-2,2- dimethyl-propionamide SC_5066
CIS-3-[8-(Ethyl-methyl-amino)-1-methyl-2-oxo-8-phenyl-1,3-diazaspi-
ro[4.5]decan-3- yl]-2,2-dimethyl-propionamide SC_5067
CIS-2,2-Dimethyl-3-(8-methylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.-
5]decan-3-yl)- propionamide SC_5069
CIS-3-(8-Ethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)--
2,2-dimethyl- propionamide SC_5070
CIS-3-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-y-
l)-2,2-dimethyl- propionamide SC_5071
CIS-3-[1-(Cyclobutyl-methyl)-8-ethylamino-2-oxo-8-phenyl-1,3-diaza-
spiro[4.5]decan- 3-yl]-2,2-dimethyl-propionamide SC_5072
CIS-3-[8-Dimethylamino-1-(oxetan-3-yl-methyl)-2-oxo-8-phenyl-1,3-
diazaspiro[4.5]decan-3-yl]-2,2-dimethyl-propionamide SC_5073
CIS-3-[1-(Cyclopropyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-
diazaspiro[4.5]decan-3-yl]-2,2-dimethyl-propionamide SC_5074
CIS-3-[8-(Ethyl-methyl-amino)-1-[(1-hydroxy-cyclobutyl)-methyl]-2--
oxo-8-phenyl-1,3-
diazaspiro[4.5]decan-3-yl]-2,2-dimethyl-propionamide SC_5076
CIS-8-Dimethylamino-3-(2,2-dimethyl-3-morpholin-4-yl-3-oxo-propyl)-
-1-[(1-hydroxy-
cyclobutyl)-methyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one SC_5077
CIS-3-[8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-2-oxo-8-p-
henyl-1,3-
diazaspiro[4.5]decan-3-yl]-N-(2-hydroxy-ethyl)-2,2-dimethyl-propionamide
SC_5078
CIS-3-[1-[(1-Cyano-cyclobutyl)-methyl]-8-dimethylamino-2-oxo-8-phe-
nyl-1,3- diazaspiro[4.5]decan-3-yl]-2,2-dimethyl-propionamide
SC_5079
CIS-8-Dimethylamino-3-[3-(1,1-dioxo-[1,4]thiazinan-4-yl)-2,2-dimet-
hyl-3-oxo-propyl]-
1-[(1-hydroxy-cyclobutyl)-methyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one
SC_5081
TRANS-3-[8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-2-oxo-8-
-phenyl-1,3- diazaspiro[4.5]decan-3-yl]-2,2-dimethyl-propionamide
SC_5082
TRANS-3-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-
-yl)-2,2- dimethyl-propionamide SC_5083
CIS-3-[1-(Cyclopropyl-methyl)-8-dimethylamino-8-(3-fluorophenyl)-2-
-oxo-1,3- diazaspiro[4.5]decan-3-yl]-N,N-dimethyl-propionamide
SC_5084
CIS-3-[1-(Cyclopropyl-methyl)-8-dimethylamino-8-(3-fluorophenyl)-2-
-oxo-1,3- diazaspiro[4.5]decan-3-yl]-2,2-dimethyl-propionamide
SC_5085
CIS-1-((1-(cyclopropylmethyl)-8-(dimethylamino)-2-oxo-8-phenyl-1,3-
- diazaspiro[4.5]decan-3-yl)methyl)cyclopropanecarboxamide SC_5086
CIS-3-((1-(cyclopropylmethyl)-8-(dimethylamino)-2-oxo-8-phenyl-1,3-
- diazaspiro[4.5]decan-3-yl)methyl)oxetane-3-carboxamide SC_5087
CIS-3-(1-(cyclopropylmethyl)-8-(methylamino)-2-oxo-8-phenyl-1,3-
diazaspiro[4.5]decan-3-yl)-2,2-dimethylpropanamide SC_5088
CIS-3-(1-(cyclopropylmethyl)-8-(dimethylamino)-2-oxo-8-phenyl-1,3-
diazaspiro[4.5]decan-3-yl)propanamide SC_5089
CIS-3-(8-(dimethylamino)-1-((1-fluorocyclopropyl)methyl)-2-oxo-8-p-
henyl-1,3- diazaspiro[4.5]decan-3-yl)-2,2-dimethylpropanamide
and the physiologically acceptable salts thereof.
[0058] According to the invention, unless expressly stated
otherwise, "--C.sub.1-C.sub.4-alkyl", "--C.sub.1-C.sub.6-alkyl" and
any other alkyl residues can be linear or branched, saturated or
unsaturated. Linear saturated alkyl includes methyl, ethyl,
n-propyl, n-butyl, n-pentyl and n-hexyl. Examples of branched
saturated alkyl include but are not limited to iso-propyl,
sec-butyl, and tert-butyl. Examples of linear unsaturated alkyl
include but are not limited to vinyl, propenyl, allyl, and
propargyl.
[0059] According to the invention, unless expressly stated
otherwise, "--C.sub.1-C.sub.4-alkyl", "--C.sub.1-C.sub.6-alkyl" and
any other alkyl residues can be unsubstituted, mono- or
polysubstituted. Examples of substituted alkyl include but are not
limited to --CH.sub.2CH.sub.2OH, --CH.sub.2CH.sub.2OCH.sub.3,
--CH.sub.2CH.sub.2CH.sub.2OCH.sub.3,
--CH.sub.2CH.sub.2S(.dbd.O).sub.2CH.sub.3,
--CH.sub.2C(.dbd.O)NH.sub.2, --C(CH.sub.3).sub.2C(.dbd.O)NH.sub.2,
--CH.sub.2C(CH.sub.3).sub.2C(.dbd.O)NH.sub.2, and
--CH.sub.2CH.sub.2C(.dbd.O)N(CH.sub.3).sub.2.
[0060] According to the invention, unless expressly stated
otherwise, "--C.sub.1-C.sub.6-alkylene-",
"--C.sub.1-C.sub.4-alkylene" and any other alkylene residue can be
unsubstituted, mono- or polysubstituted. Examples of saturated
alkylene include but are not limited to --CH.sub.2--,
--CH(CH.sub.3)--, --C(CH.sub.3).sub.2--, --CH.sub.2CH.sub.2--,
--CH(CH.sub.3)CH.sub.2--, --CH.sub.2CH(CH.sub.3)--,
--CH(CH.sub.3)--CH(CH.sub.3)--, --C(CH.sub.3).sub.2CH.sub.2--,
--CH.sub.2C(CH.sub.3).sub.2--, --CH(CH.sub.3)C(CH.sub.3).sub.2--,
--C(CH.sub.3).sub.2CH(CH.sub.3)--,
C(CH.sub.3).sub.2C(CH.sub.3).sub.2--, --CH.sub.2CH.sub.2CH.sub.2--,
and --C(CH.sub.3).sub.2CH.sub.2CH.sub.2--. Examples of unsaturated
alkylene include but are not limited to --CH.dbd.CH--,
--C.ident.C--, --C(CH.sub.3).dbd.CH--, --CH.dbd.C(CH.sub.3)--,
--C(CH.sub.3).dbd.C(CH.sub.3)--, --CH.sub.2CH.dbd.CH--,
--CH.dbd.CHCH.sub.2--, --CH.dbd.CH--CH.dbd.CH--, and
--CH.dbd.CH--C.ident.C--.
[0061] According to the invention, unless expressly stated
otherwise, "--C.sub.1-C.sub.6-alkylene-",
"--C.sub.1-C.sub.4-alkylene" and any other alkylene residue can be
unsubstituted, mono- or polysubstituted. Examples of substituted
--C.sub.1-C.sub.6-alkylene-include but are not limited to --CHF--,
--CF.sub.2--, --CHOH-- and --C(.dbd.O)--.
[0062] According to the invention, moieties may be connected
through --C.sub.1-C.sub.6-alkylene-, i.e. the moieties may not be
directly bound to the core structure of compound according to
general formula (I), but may be connected to the core structure of
compound according to general formula (I) or its periphery through
a --C.sub.1-C.sub.6-alkylene-linker.
[0063] According to the invention, "3-12-membered cycloalkyl
moiety" means a non-aromatic, monocyclic, bicyclic or tricyclic
moiety comprising 3 to 12 ring carbon atoms but no heteroatoms in
the ring. Examples of preferred saturated 3-12-membered cycloalkyl
moieties according to the invention include but are not limited to
cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane,
cyclooctane, hydrindane, and decaline. Examples of preferred
unsaturated 3-12-membered cycloalkyl moiety moieties according to
the invention include but are not limited to cyclopropene,
cyclobutene, cyclopentene, cyclopentadiene, cyclohexene,
1,3-cyclohexadiene, and 1,4-cyclohexadiene. The 3-12-membered
cycloalkyl moiety, which is bonded to the compound according to the
invention, in its periphery may optionally be condensed with a
3-12-membered heterocycloalkyl moiety, saturated or unsaturated,
unsubstituted, mono- or polysubstituted; and/or with a
6-14-membered aryl moiety, unsubstituted, mono- or polysubstituted;
and/or with a 5-14-membered heteroaryl moiety, unsubstituted, mono-
or polysubstituted. Under these circumstances, the ring atoms of
the condensed moieties are not included in the 3 to 12 ring atoms
of the 3-12-membered cycloalkyl moiety. Examples of 3-12-membered
cycloalkyl moieties condensed with 3-12-membered heterocycloalkyl
moieties include but are not limited to octahydro-1H-indol,
decahydroquinoline, decahydroisoquinoline,
octahydro-2H-benzo[b][1,4]oxazin, and decahydroquinoxalin, which in
each case are connected through the 3-12-membered cycloalkyl
moiety. Examples of 3-12-membered cycloalkyl moieties condensed
with 6-14-membered aryl moieties include but are not limited to
2,3-dihydro-1H-indene and tetraline, which in each case are
connected through the 3-12-membered cycloalkyl moiety. Examples of
3-12-membered cycloalkyl moieties condensed with 5-14-membered
heteroaryl moieties include but are not limited to
5,6,7,8-tetrahydroquinoline and 5,6,7,8-tetrahydroquinazoline,
which in each case are connected through the 3-12-membered
cycloalkyl moiety.
[0064] According to the invention, the 3-12-membered cycloalkyl
moiety may optionally be connected through
--C.sub.1-C.sub.6-alkylene-, i.e. the 3-12-membered cycloalkyl
moiety may not be directly bound to the compound according to
general formula (I) but may be connected thereto through a
--C.sub.1-C.sub.6-alkylene-linker. Examples include but are not
limited to --CH.sub.2-cyclopropyl, --CH.sub.2-cyclobutyl,
--CH.sub.2-cyclopentyl, --CH.sub.2-cyclohexyl,
--CH.sub.2CH.sub.2-cyclopropyl, --CH.sub.2CH.sub.2-cyclobutyl,
--CH.sub.2CH.sub.2-cyclopentyl, and
--CH.sub.2CH.sub.2-cyclohexyl.
[0065] According to the invention, unless expressly stated
otherwise, the 3-12-membered cycloalkyl moiety can be
unsubstituted, mono- or polysubstituted. Examples of substituted
3-12-membered cycloalkyl moieties include but are not limited to
--CH.sub.2-1-hydroxy-cyclobutyl.
[0066] According to the invention, "3-12-membered heterocycloalkyl
moiety" means a non-aromatic, monocyclic, bicyclic or tricyclic
moiety comprising 3 to 12 ring atoms, wherein each cycle comprises
independently of one another 1, 2, 3, 4 or more heteroatoms
independently of one another selected from the group consisting of
nitrogen, oxygen and sulfur, whereas sulfur may be oxidized
(S(.dbd.O) or (S(.dbd.O).sub.2), whereas the remaining ring atoms
are carbon atoms, and whereas bicyclic or tricyclic systems may
share common heteroatom(s). Examples of preferred saturated
3-12-membered heterocycloalkyl moieties according to the invention
include but are not limited to aziridin, azetidine, pyrrolidine,
imidazolidine, pyrazolidine, piperidine, piperazine, triazolidine,
tetrazolidine, oxiran, oxetane, tetrahydrofurane, tetrahydropyrane,
thiirane, thietane, tetrahydrothiophene, diazepane, oxazolidine,
isoxazolidine, thiazolidine, isothiazolidine, thiadiazolidine,
morpholine, thiomorpholine. Examples of preferred unsaturated
3-12-membered heterocycloalkyl moiety moieties according to the
invention include but are not limited to oxazoline, pyrazoline,
imidazoline, isoxazoline, thiazoline, isothiazoline; and
dihydropyran. The 3-12-membered heterocycloalkyl moiety, which is
bonded to the compound according to the invention, in its periphery
may optionally be condensed with a 3-12-membered cycloalkyl moiety,
saturated or unsaturated, unsubstituted, mono- or polysubstituted;
and/or with a 6-14-membered aryl moiety, unsubstituted, mono- or
polysubstituted; and/or with a 5-14-membered heteroaryl moiety,
unsubstituted, mono- or polysubstituted. Under these circumstances,
the ring atoms of the condensed moieties are not included in the 3
to 12 ring atoms of the 3-12-membered heterocycloalkyl moieties.
Examples of 3-12-membered heterocycloalkyl moieties condensed with
3-12-membered cycloalkyl moieties include but are not limited to
octahydro-1H-indol, decahydroquinoline, decahydroisoquinoline,
octahydro-2H-benzo[b][1,4]oxazin, and decahydroquinoxalin, which in
each case are connected through the 3-12-membered heterocycloalkyl
moiety. An examples of a 3-12-membered heterocycloalkyl moiety
condensed with a 6-14-membered aryl moiety includes but is not
limited to 1,2,3,4-tetrahydroquinoline, which is connected through
the 3-12-membered heterocycloalkyl moiety. An example of a
3-12-membered heterocycloalkyl moiety condensed with a
5-14-membered heteroaryl moieties includes but is not limited to
5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyrazine, which is
connected through the 3-12-membered heterocycloalkyl moiety.
[0067] According to the invention, the 3-12-membered
heterocycloalkyl moiety may optionally be connected through
--C.sub.1-C.sub.6-alkylene-, i.e. the 3-12-membered
heterocycloalkyl moiety may not be directly bound to the compound
according to general formula (I) but may be connected thereto
through a --C.sub.1-C.sub.6-alkylene-linker. Said linker may be
connected to a carbon ring atom or to a hetero ring atom of the
3-12-membered heterocycloalkyl moiety. Examples include but are not
limited to --CH.sub.2-oxetane, --CH.sub.2-pyrrolidine,
--CH.sub.2-piperidine, --CH.sub.2-morpholine,
--CH.sub.2CH.sub.2-oxetane, --CH.sub.2CH.sub.2-pyrrolidine,
--CH.sub.2CH.sub.2-piperidine, and
--CH.sub.2CH.sub.2-morpholine.
[0068] According to the invention, unless expressly stated
otherwise, the 3-12-membered heterocycloalkyl moiety can be
unsubstituted, mono- or polysubstituted. Examples of substituted
3-12-membered heterocycloalkyl moieties include but are not limited
to 2-carboxamido-N-pyrrolidinyl-, 3,4-dihydroxy-N-pyrrolidinyl,
3-hydroxy-N-pyrimidinyl, 3,4-dihydroxy-N-pyrimidinyl,
3-oxo-N-piperazinyl, -tetrahydro-2H-thiopyranyl dioxide and
thiomorpholinyl dioxide.
[0069] According to the invention, "6-14-membered aryl moiety"
means an aromatic, monocyclic, bicyclic or tricyclic moiety
comprising 6 to 14 ring carbon atoms but no heteroatoms in the
ring. Examples of preferred 6-14-membered aryl moieties according
to the invention include but are not limited to benzene,
naphthalene, anthracen, and phenanthren. The 6-14-membered aryl
moiety, which is bonded to the compound according to the invention,
in its periphery may optionally be condensed with a 3-12-membered
cycloalkyl moiety, saturated or unsaturated, unsubstituted, mono-
or polysubstituted; and/or with a 3-12-membered heterocycloalkyl
moiety, saturated or unsaturated, unsubstituted, mono- or
polysubstituted; and/or with a 5-14-membered heteroaryl moiety,
unsubstituted, mono- or polysubstituted. Under these circumstances,
the ring atoms of the condensed moieties are not included in the 6
to 14 ring carbon atoms of the 6-14-membered heterocycloalkyl
moieties. Examples of 6-14-membered aryl moieties condensed with
3-12-membered cycloalkyl moieties include but are not limited to
2,3-dihydro-1H-indene and tetraline, which in each case are
connected through the 6-14-membered aryl moiety. An example of a
6-14-membered aryl moiety condensed with a 3-12-membered
heterocycloalkyl moiety includes but is not limited to
1,2,3,4-tetrahydroquinoline, which is connected through the
6-14-membered aryl moiety. Examples of 6-14-membered aryl moieties
condensed with 5-14-membered heteroaryl moieties include but are
not limited to quinoline, isoquinoline, phenazine and phenoxacine,
which in each case are connected through the 6-14-membered aryl
moiety.
[0070] According to the invention, the 6-14-membered aryl moiety
may optionally be connected through --C.sub.1-C.sub.6-alkylene-,
i.e. the 6-14-membered aryl moiety may not be directly bound to the
compound according to general formula (I) but may be connected
thereto through a --C.sub.1-C.sub.6-alkylene-linker. Said linker
may be connected to a carbon ring atom or to a hetero ring atom of
the 6-14-membered aryl moiety. Examples include but are not limited
to --CH.sub.2--C.sub.6H.sub.5, --CH.sub.2CH.sub.2--C.sub.6H.sub.5
and --CH.dbd.CH--C.sub.6H.sub.5.
[0071] According to the invention, unless expressly stated
otherwise, the 6-14-membered aryl moiety can be unsubstituted,
mono- or polysubstituted. Examples of substituted 6-14-membered
aryl moieties include but are not limited to 2-fluorophenyl,
3-fluorophenyl, 2-methoxyphenyl and 3-methoxyphenyl.
[0072] According to the invention, "5-14-membered heteroaryl
moiety" means an aromatic, monocyclic, bicyclic or tricyclic moiety
comprising 6 to 14 ring atoms, wherein each cycle comprises
independently of one another 1, 2, 3, 4 or more heteroatoms
independently of one another selected from the group consisting of
nitrogen, oxygen and sulfur, whereas the remaining ring atoms are
carbon atoms, and whereas bicyclic or tricyclic systems may share
common heteroatom(s). Examples of preferred 5-14-membered
heteroaryl moieties according to the invention include but are not
limited to pyrrole, pyrazole, imidazole, triazole, tetrazole,
furane, thiophene, oxazole, isoxazole, thiazole, isothiazole,
pyridine, pyridazine, pyrimidine, pyrazine, indolicine,
9H-chinolicine, 1,8-naphthyridine, purine, imidazo[1,2-a]pyrazine,
and pteridine. The 5-14-membered heteroaryl moiety, which is bonded
to the compound according to the invention, in its periphery may
optionally be condensed with a 3-12-membered cycloalkyl moiety,
saturated or unsaturated, unsubstituted, mono- or polysubstituted;
and/or with a 3-12-membered heterocycloalkyl moiety, saturated or
unsaturated, unsubstituted, mono- or polysubstituted; and/or with a
6-14-membered aryl moiety, unsubstituted, mono- or polysubstituted.
Under these circumstances, the ring atoms of the condensed moieties
are not included in the 6 to 14 ring carbon atoms of the
6-14-membered heterocycloalkyl moieties. Examples of 5-14-membered
heteroaryl moieties condensed with 3-12-membered cycloalkyl
moieties include but are not limited to 5,6,7,8-tetrahydroquinoline
and 5,6,7,8-tetrahydroquinazoline, which in each case are connected
through the 5-14-membered heteroaryl moiety. An examples of a
5-14-membered heteroaryl moiety condensed with a 3-12-membered
heterocycloalkyl moiety includes but is not limited to
5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyrazine, which is
connected through the 5-14-membered heteroaryl moiety. Examples of
5-14-membered heteroaryl moieties condensed with 6-14-membered aryl
moieties include but are not limited to quinoline, isoquinoline,
phenazine and phenoxacine, which in each case are connected through
the 5-14-membered heteroaryl moiety.
[0073] According to the invention, the 5-14-membered heteroaryl
moiety may optionally be connected through
--C.sub.1-C.sub.6-alkylene-, i.e. the 5-14-membered heteroaryl
moiety may not be directly bound to the compound according to
general formula (I) but may be connected thereto through a
--C.sub.1-C.sub.6-alkylene-linker. Said linker may be connected to
a carbon ring atom or to a hetero ring atom of the 5-14-membered
heteroaryl moiety. Examples include but are not limited to
--CH.sub.2-oxazole, --CH.sub.2-- isoxazole, --CH.sub.2-imidazole,
--CH.sub.2-pyridine, --CH.sub.2-pyrimidine, --CH.sub.2-pyridazine,
--CH.sub.2CH.sub.2-oxazole, --CH.sub.2CH.sub.2-isoxazole,
--CH.sub.2CH.sub.2-imidazole, --CH.sub.2CH.sub.2-pyridine,
--CH.sub.2CH.sub.2-pyrimidine, and
--CH.sub.2CH.sub.2-pyridazine.
[0074] According to the invention, unless expressly stated
otherwise, the 5-14-membered heteroaryl moiety can be
unsubstituted, mono- or polysubstituted. Examples of 5-14-membered
heteroaryl moieties include but are not limited to
2-methoxy-4-pyridinyl, 2-methoxy-5-pyridinyl,
3-methoxy-4-pyridinyl, 3-methoxy-6-pyridinyl,
4-methoxy-2-pyridinyl, 2-methylsulfonyl-5-pyridinyl,
3-methylsulfonyl-6-pyridinyl, 3-methoxy-6-pyridazinyl,
2-nitrilo-5-pyrimidinyl, 4-hydroxy-2-pyrimidinyl,
4-methoxy-pyrimidinyl, and 2-methoxy-6-pyrazinyl.
[0075] Preferably, the compounds according to the invention have a
structure according to general formula (I')
##STR00011##
wherein R.sup.1 to R.sup.5, R.sup.7 to R.sup.20, and X are defined
as above, or a physiologically acceptable salt thereof.
[0076] In one preferred embodiment, the excess of the cis-isomer so
designated is at least 50% de, more preferably at least 75% de, yet
more preferably at least 90% de, most preferably at least 95% de
and in particular at least 99% de.
[0077] In particularly preferred embodiments, the compound
according to the invention has a structure according to general
formula (IX)
##STR00012##
wherein R.sup.C means --H or --OH; R.sup.D means --H or --F;
R.sup.5 means --H, --CH.sub.3, or --CH.sub.2CH.sub.2--OH; R.sup.6
means --H or --CH.sub.3; and R.sup.7 means --CH.sub.3 and R.sup.8
means --CH.sub.3; or R.sup.7 and R.sup.8 together with the carbon
atom to which they are attached form a cyclopropyl ring.
[0078] When within the moiety corresponding to residue R.sup.4 the
index is 1, the ring is a cyclopropyl ring. When within the moiety
corresponding to residue R.sup.4 the index is 2, the ring is a
cyclobutyl ring.
[0079] In a preferred embodiment, the compounds according to the
invention are in the form of the free bases.
[0080] In another preferred embodiment, the compounds according to
the invention are in the form of the physiologically acceptable
salts.
[0081] For the purposes of the description, a "salt" is to be
understood as being any form of the compound in which it assumes an
ionic form or is charged and is coupled with a counter-ion (a
cation or anion) or is in solution. The term is also to be
understood as meaning complexes of the compound with other
molecules and ions, in particular complexes which are associated
via ionic interactions. Preferred salts are physiologically
acceptable, in particular physiologically acceptable salts with
anions or acids or also a salt formed with a physiologically
acceptable acid.
[0082] Physiologically acceptable salts with anions or acids are
salts of the particular compound in question with inorganic or
organic acids which are physiologically acceptable, in particular
when used in humans and/or mammals. Examples of physiologically
acceptable salts of particular acids include but are not limited to
salts of hydrochloric acid, sulfuric acid, and acetic acid.
[0083] The invention also includes isotopic isomers of a compound
according to the invention, wherein at least one atom of the
compound is replaced by an isotope of the respective atom which is
different from the naturally predominantly occurring isotope, as
well as any mixtures of isotopic isomers of such a compound.
Preferred isotopes are .sup.2H (deuterium), .sup.3H (tritium),
.sup.13C and .sup.14C.
[0084] Certain compounds according to the invention are useful for
modulating a pharmacodynamic response from one or more opioid
receptors (mu, delta, kappa, NOP/ORL-1) either centrally or
peripherally, or both. The pharmacodynamic response may be
attributed to the compound either stimulating (agonizing) or
inhibiting (antagonizing) the one or more receptors. Certain
compounds according to the invention may antagonize one opioid
receptor, while also agonizing one or more other receptors.
Compounds according to the invention having agonist activity may be
either full agonists or partial agonists.
[0085] As used herein, compounds that bind to receptors and mimic
the regulatory effects of endogenous ligands are defined as
"agonists". Compounds that bind to a receptor but produce no
regulatory effect, but rather block the binding of ligands to the
receptor, are defined as "antagonists".
[0086] In certain embodiments, the compounds according to the
invention are agonists at the mu opioid (MOP) and/or kappa opioid
(KOP) and/or delta opioid (DOP) and/or nociceptin opioid
(NOP/ORL-1) receptors.
[0087] The compounds according to the invention potently bind to
the MOP and/or KOP and/or DOP and/or NOP receptors.
[0088] The compounds according to the invention can be modulators
at the MOP and/or KOP and/or DOP and/or NOP receptors, and
therefore the compounds according to the invention can be
used/administered to treat, ameliorate, or prevent pain.
[0089] In some embodiments, the compounds according to the
invention are agonists of one or more opioid receptors. In some
embodiments, the compounds according to the invention are agonists
of the MOP and/or KOP and/or DOP and/or NOP receptors.
[0090] In some embodiments, the compounds according to the
invention are antagonists of one or more opioid receptors. In some
embodiments, the compounds according to the invention are
antagonists of the MOP and/or KOP and/or DOP and/or NOP
receptors.
[0091] In some embodiments, the compounds according to the
invention have both, (i) agonist activity at the NOP receptor; and
(ii) agonist activity at one or more of the MOP, KOP, and DOP
receptors.
[0092] In some embodiments, the compounds according to the
invention have both, (i) agonist activity at the NOP receptor; and
(ii) antagonist activity at one or more of the MOP, KOP, and DOP
receptors.
[0093] In some embodiments, the compounds according to the
invention have both, (i) antagonist activity at the NOP receptor;
and (ii) agonist activity at one or more of the MOP, KOP, and DOP
receptors.
[0094] In some embodiments, the compounds according to the
invention have both, (i) antagonist activity at the NOP receptor;
and (ii) antagonist activity at one or more of the MOP, KOP, and
DOP receptors.
[0095] In some embodiments, preferably with respect to receptors of
the peripheral nervous system, the compounds according to the
invention have selective agonist activity at the NOP receptor. In
some embodiments, preferably with respect to receptors of the
peripheral nervous system, the compounds according to the invention
[0096] have agonist activity at the NOP receptor, but no
significant activity at the MOP receptor; [0097] have agonist
activity at the NOP receptor, but no significant activity at the
KOP receptor; [0098] have agonist activity at the NOP receptor, but
no significant activity at the DOP receptor; [0099] have agonist
activity at the NOP receptor, but no significant activity at the
MOP receptor as well as no significant activity at the KOP
receptor; [0100] have agonist activity at the NOP receptor, but no
significant activity at the MOP receptor as well as no significant
activity at the DOP receptor; or [0101] have agonist activity at
the NOP receptor, but no significant activity at the MOP receptor
as well as no significant activity at the KOP receptor as well as
no significant activity at the DOP receptor.
[0102] In some embodiments, preferably with respect to receptors of
the peripheral nervous system, the compounds according to the
invention have balanced agonist activity at the NOP receptor as
well as at the MOP receptor. In some embodiments, preferably with
respect to receptors of the peripheral nervous system, the
compounds according to the invention [0103] have agonist activity
at the NOP receptor as well as agonist activity at the MOP
receptor; [0104] have agonist activity at the NOP receptor as well
as agonist activity at the MOP receptor as well as agonist activity
at the KOP receptor; [0105] have agonist activity at the NOP
receptor as well as agonist activity at the MOP receptor as well as
agonist activity at the DOP receptor; [0106] can be regarded as
opioid pan agonists, i.e. have agonist activity at the NOP receptor
as well as agonist activity at the MOP receptor as well as agonist
activity at the KOP receptor as well as agonist activity at the DOP
receptor; [0107] have agonist activity at the NOP receptor as well
as agonist activity at the MOP receptor, but no significant
activity at the KOP receptor; [0108] have agonist activity at the
NOP receptor as well as agonist activity at the MOP receptor, but
no significant activity at the DOP receptor; or [0109] have agonist
activity at the NOP receptor as well as agonist activity at the MOP
receptor, but no significant activity at the KOP receptor as well
as no significant activity at the DOP receptor.
[0110] In some embodiments, preferably with respect to receptors of
the peripheral nervous system, the compounds according to the
invention have balanced agonist activity at the NOP receptor as
well as at the KOP receptor. In some embodiments, preferably with
respect to receptors of the peripheral nervous system, the
compounds according to the invention [0111] have agonist activity
at the NOP receptor as well as agonist activity at the KOP
receptor; [0112] have agonist activity at the NOP receptor as well
as agonist activity at the KOP receptor as well as agonist activity
at the MOP receptor; [0113] have agonist activity at the NOP
receptor as well as agonist activity at the KOP receptor as well as
agonist activity at the DOP receptor; [0114] have agonist activity
at the NOP receptor as well as agonist activity at the KOP
receptor, but no significant activity at the MOP receptor; [0115]
have agonist activity at the NOP receptor as well as agonist
activity at the KOP receptor, but no significant activity at the
DOP receptor; or [0116] have agonist activity at the NOP receptor
as well as agonist activity at the KOP receptor, but no significant
activity at the MOP receptor as well as no significant activity at
the DOP receptor.
[0117] In some embodiments, preferably with respect to receptors of
the peripheral nervous system, the compounds according to the
invention have balanced agonist activity at the NOP receptor as
well as at the DOP receptor. In some embodiments, preferably with
respect to receptors of the peripheral nervous system, the
compounds according to the invention [0118] have agonist activity
at the NOP receptor as well as agonist activity at the DOP
receptor; [0119] have agonist activity at the NOP receptor as well
as agonist activity at the DOP receptor, but no significant
activity at the MOP receptor; [0120] have agonist activity at the
NOP receptor as well as agonist activity at the DOP receptor, but
no significant activity at the KOP receptor; or [0121] have agonist
activity at the NOP receptor as well as agonist activity at the DOP
receptor, but no significant activity at the MOP receptor as well
as no significant activity at the KOP receptor.
[0122] In some embodiments, preferably with respect to receptors of
the peripheral nervous system, the compounds according to the
invention have selective agonist activity at the KOP receptor. In
some embodiments, preferably with respect to receptors of the
peripheral nervous system, the compounds according to the invention
[0123] have agonist activity at the KOP receptor, but no
significant activity at the MOP receptor; [0124] have agonist
activity at the KOP receptor, but no significant activity at the
NOP receptor; [0125] have agonist activity at the KOP receptor, but
no significant activity at the DOP receptor; [0126] have agonist
activity at the KOP receptor, but no significant activity at the
MOP receptor as well as no significant activity at the NOP
receptor; [0127] have agonist activity at the KOP receptor, but no
significant activity at the MOP receptor as well as no significant
activity at the DOP receptor; or [0128] have agonist activity at
the KOP receptor, but no significant activity at the MOP receptor
as well as no significant activity at the NOP receptor as well as
no significant activity at the DOP receptor.
[0129] In some embodiments, preferably with respect to receptors of
the peripheral nervous system, the compounds according to the
invention have agonist activity at the MOP receptor, agonist
activity at the KOP receptor, and antagonist activity at the DOP
receptor. In some embodiments, preferably with respect to receptors
of the peripheral nervous system, the compounds according to the
invention [0130] have agonist activity at the MOP receptor as well
as agonist activity at the KOP receptor as well as antagonist
activity at the DOP receptor; [0131] have agonist activity at the
MOP receptor as well as agonist activity at the KOP receptor as
well as antagonist activity at the DOP receptor as well as agonist
activity at the NOP receptor; [0132] have agonist activity at the
MOP receptor as well as agonist activity at the KOP receptor as
well as antagonist activity at the DOP receptor as well as
antagonist activity at the NOP receptor; or [0133] have agonist
activity at the MOP receptor as well as agonist activity at the KOP
receptor as well as antagonist activity at the DOP receptor, no
significant activity at the NOP receptor.
[0134] In some embodiments, preferably with respect to receptors of
the central nervous system, the compounds according to the
invention have selective agonist activity at the NOP receptor. In
some embodiments, preferably with respect to receptors of the
central nervous system, the compounds according to the invention
[0135] have agonist activity at the NOP receptor, but no
significant activity at the MOP receptor; [0136] have agonist
activity at the NOP receptor, but no significant activity at the
KOP receptor; [0137] have agonist activity at the NOP receptor, but
no significant activity at the DOP receptor; [0138] have agonist
activity at the NOP receptor, but no significant activity at the
MOP receptor as well as no significant activity at the KOP
receptor; [0139] have agonist activity at the NOP receptor, but no
significant activity at the MOP receptor as well as no significant
activity at the DOP receptor; or [0140] have agonist activity at
the NOP receptor, but no significant activity at the MOP receptor
as well as no significant activity at the KOP receptor as well as
no significant activity at the DOP receptor.
[0141] In some embodiments, preferably with respect to receptors of
the central nervous system, the compounds according to the
invention have selective antagonist activity at the NOP receptor.
In some embodiments, preferably with respect to receptors of the
central nervous system, the compounds according to the invention
[0142] have antagonist activity at the NOP receptor, but no
significant activity at the MOP receptor; [0143] have antagonist
activity at the NOP receptor, but no significant activity at the
KOP receptor; [0144] have antagonist activity at the NOP receptor,
but no significant activity at the DOP receptor; [0145] have
antagonist activity at the NOP receptor, but no significant
activity at the MOP receptor as well as no significant activity at
the KOP receptor; [0146] have antagonist activity at the NOP
receptor, but no significant activity at the MOP receptor as well
as no significant activity at the DOP receptor; or [0147] have
antagonist activity at the NOP receptor, but no significant
activity at the MOP receptor as well as no significant activity at
the KOP receptor as well as no significant activity at the DOP
receptor.
[0148] In some embodiments, preferably with respect to receptors of
the central nervous system, the compounds according to the
invention have antagonist activity at the NOP receptor as well as
agonist activity at the DOP receptor. In some embodiments,
preferably with respect to receptors of the central nervous system,
the compounds according to the invention [0149] have antagonist
activity at the NOP receptor as well as agonist activity at the DOP
receptor; [0150] have antagonist activity at the NOP receptor as
well as agonist activity at the DOP receptor, but no significant
activity at the MOP receptor; [0151] have antagonist activity at
the NOP receptor as well as agonist activity at the DOP receptor,
but no significant activity at the KOP receptor; or [0152] have
antagonist activity at the NOP receptor as well as agonist activity
at the DOP receptor, but no significant activity at the MOP
receptor as well as no significant activity at the KOP
receptor.
[0153] For the purpose of the specification, "no significant
activity" means that the activity (agonist/antagonist) of the given
compound at this receptor is lower by a factor of 1000 or more
compared to its activity (agonist/antagonist) at one or more of the
other opioid receptors.
[0154] A further aspect of the invention relates to the compounds
according to the invention as medicaments.
[0155] A further aspect of the invention relates to the compounds
according to the invention for use in the treatment of pain. A
further aspect of the invention relates to a method of treating
pain comprising the administration of a pain alleviating amount of
a compound according to the invention to a subject in need thereof,
preferably to a human. The pain is preferably acute or chronic. The
pain is preferably nociceptive or neuropathic.
[0156] A further aspect of the invention relates to the compounds
according to the invention for use in the treatment of
neurodegenerative disorders, neuroinflammatory disorders,
neuropsychiatric disorders, and substance abuse/dependence. A
further aspect of the invention relates to a method of treating any
one of the aforementioned disorders, diseases or conditions
comprising the administration of a therapeutically effective amount
of a compound according to the invention to a subject in need
thereof, preferably to a human.
[0157] Another aspect of the invention relates to a pharmaceutical
composition which contains a physiologically acceptable carrier and
at least one compound according to the invention,
[0158] Preferably, the composition according to the invention is
solid, liquid or pasty; and/or contains the compound according to
the invention in an amount of from 0.001 to 99 wt. %, preferably
from 1.0 to 70 wt. %, based on the total weight of the
composition.
[0159] The pharmaceutical composition according to the invention
can optionally contain suitable additives and/or auxiliary
substances and/or optionally further active ingredients.
[0160] Examples of suitable physiologically acceptable carriers,
additives and/or auxiliary substances are fillers, solvents,
diluents, colorings and/or binders. These substances are known to
the person skilled in the art (see H. P. Fiedler, Lexikon der
Hilfsstoffe fur Pharmazie, Kosmetik and angrenzende Gebiete, Editio
Cantor Aulendoff).
[0161] The pharmaceutical composition according to the invention
contains the compound according to the invention in an amount of
preferably from 0.001 to 99 wt. %, more preferably from 0.1 to 90
wt. %, yet more preferably from 0.5 to 80 wt. %, most preferably
from 1.0 to 70 wt. % and in particular from 2.5 to 60 wt. %, based
on the total weight of the pharmaceutical composition.
[0162] The pharmaceutical composition according to the invention is
preferably for systemic, topical or local administration,
preferably for oral administration.
[0163] Another aspect of the invention relates to a pharmaceutical
dosage form which contains the pharmaceutical composition according
to the invention.
[0164] In one preferred embodiment, the pharmaceutical dosage form
according to the invention is produced for administration twice
daily, for administration once daily or for administration less
frequently than once daily. Administration is preferably systemic,
in particular oral.
[0165] The pharmaceutical dosage form according to the invention
can be administered, for example, as a liquid dosage form in the
form of injection solutions, drops or juices, or as a semi-solid
dosage form in the form of granules, tablets, pellets, patches,
capsules, plasters/spray-on plasters or aerosols. The choice of
auxiliary substances etc. and the amounts thereof to be used depend
on whether the form of administration is to be administered orally,
perorally, parenterally, intravenously, intraperitoneally,
intradermally, intramuscularly, intranasally, buccally, rectally or
locally, for example to the skin, the mucosa or into the eyes.
[0166] Pharmaceutical dosage forms in the form of tablets, dragees,
capsules, granules, drops, juices and syrups are suitable for oral
administration, and solutions, suspensions, readily reconstitutable
dry preparations and also sprays are suitable for parenteral,
topical and inhalatory administration. Compounds according to the
invention in a depot, in dissolved form or in a plaster, optionally
with the addition of agents promoting penetration through the skin,
are suitable percutaneous administration preparations.
[0167] The amount of the compounds according to the invention to be
administered to the patient varies in dependence on the weight of
the patient, on the type of administration, on the indication and
on the severity of the disease. Usually, from 0.00005 mg/kg to 50
mg/kg, preferably from 0.001 mg/kg to 10 mg/kg, of at least one
compound according to the invention is administered.
[0168] Another aspect of the invention relates to a process for the
preparation of the compounds according to the invention. Suitable
processes for the synthesis of the compounds according to the
invention are known in principle to the person skilled in the
art.
[0169] Preferred synthesis routes are described below:
[0170] The compounds according to the invention can be obtained via
different synthesis routes. Depending on the synthesis route,
different intermediates are prepared and subsequently further
reacted.
[0171] In a preferred embodiment, the synthesis of the compounds
according to the invention proceeds via a synthesis route which
comprises the preparation of an intermediate according to general
formula (IIIa):
##STR00013##
wherein R.sup.1, R.sup.2 and R.sup.3 are defined as above.
[0172] In another preferred embodiment, the synthesis of the
compounds according to the invention proceeds via a synthesis route
which comprises the preparation of an intermediate according to
general formula (IIIb):
##STR00014##
wherein R.sup.1, R.sup.2 and R.sup.3 are defined as above and PG is
a protecting group.
[0173] Preferably the protecting group is -p-methoxybenzyl.
Therefore, in another preferred embodiment, the synthesis of the
compounds according to the invention proceeds via a synthesis route
which comprises the preparation of an intermediate according to
general formula (IIIc):
##STR00015##
wherein R.sup.1, R.sup.2 and R.sup.3 are defined as above.
[0174] As already indicated, in general formula (IIIc), the
-p-methoxybenzyl moiety represents a protecting group which can be
cleaved in the course of the synthesis route.
[0175] In yet another preferred embodiment, the synthesis of the
compounds according to the invention proceeds via a synthesis route
which comprises the preparation of [0176] an intermediate according
to general formula (IIIa) and according to general formula (IIIb);
or [0177] an intermediate according to general formula (IIIa) and
according to general formula (IIIc); or [0178] an intermediate
according to general formula (IIIb) and according to general
formula (IIIc); or [0179] an intermediate according to general
formula (IIIa), according to general formula (IIIb) and according
to general formula (IIIc).
[0180] The following examples further illustrate the invention but
are not to be construed as limiting its scope.
EXAMPLES
[0181] "RT" means room temperature (23.+-.7 OC), "M" are
indications of concentration in mol/I, "aq." means aqueous, "sat."
means saturated, "sol." means solution, "conc." means
concentrated.
Further Abbreviations
[0182] brine saturated aqueous sodium chloride solution CC column
chromatography cHex cyclohexane DCM dichloromethane
DIPEA N,N-diisopropylethylamine
DMF N,N-dimethylformamide
Et Ethyl
[0183] ether diethyl ether EE ethyl acetate EtOAc ethyl acetate
EtOH ethanol h hour(s) H.sub.2O water HATU
O-(7-aza-benzotriazol-1-yl)-N,N,N',N'-tetramethyluroniumhexafluorophospha-
te LDA Lithium-di-isoproyl-amid
Me Methyl
[0184] m/z mass-to-charge ratio MeOH methanol MeCN acetonitrile min
minutes MS mass spectrometry NBS N-bromo-succinimide NEt.sub.3
triethylamine Pd.sub.2(dba).sub.3
tris(dibenzylideneacetone)dipalladium(0)
PE Petrol Ether (60 80.degree. C.)
[0185] RM reaction mixture RT room temperature T3P
2,4,6-Tripropyl-1,3,5,2,4,6-trioxatriphosphorinane-2,4,6-trioxide
tBME tert-.butyl methyl ether THF tetrahydrofuran v/v volume to
volume w/w weight to weight XantPhos
4,5-bis(diphenylphosphino)-9,9-dimethylxanthene
[0186] The yields of the compounds prepared were not optimised. All
temperatures are uncorrected.
[0187] All starting materials, which are not explicitly described,
were either commercially available (the details of suppliers such
as for example Acros, Aldrich, Bachem, Butt park, Enamine, Fluka,
Lancaster, Maybridge, Merck, Sigma, TCI, Oakwood, etc. can be found
in the Symyx.RTM. Available Chemicals Database of MDL, San Ramon,
US or the SciFinder.RTM. Database of the ACS, Washington D.C., US,
respectively, for example) or the synthesis thereof has already
been described precisely in the specialist literature (experimental
guidelines can be found in the Reaxys.RTM. Database of Elsevier,
Amsterdam, NL or the SciFinder.RTM. Database of the ACS, Washington
D.C., US, repspectively, for example) or can be prepared using the
conventional methods known to the person skilled in the art.
[0188] The mixing ratios of solvents or eluents for chromatography
are specified in v/v.
[0189] All the intermediate products and exemplary compounds were
analytically characterised by mass spectrometry (MS, m/z for
[M+H]+). In addition .sup.1H-NMR and .sup.13C spectroscopy was
carried out for all the exemplary compounds and selected
intermediate products.
[0190] Remark Regarding Stereochemistry
[0191] CIS refers to the relative configuration of compounds
described herein, in which both nitrogen atoms are drawn on the
same face of the cyclohexane ring as described in the following
exemplary structure. Two depictions are possible:
##STR00016##
[0192] TRANS refers to compounds, in which both nitrogen atoms are
on opposite faces of the cyclohexane ring as described in the
following exemplary structure. Two depictions are possible:
##STR00017##
Synthesis of Intermediates
Synthesis of INT-799:
CIS-8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-8-phenyl-1,3-diazas-
piro[4.5]decan-2-one
##STR00018##
[0193] Step 1:
CIS-1-((1-(benzyloxy)cyclobutyl)methyl)-3-(3,4-dimethoxybenzyl)-8-(dimeth-
ylamino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one
[0194] NaOH (1.42 g, 35.5 mmol) was added to a solution of
CIS-3-(3,4-dimethoxybenzyl)-8-(dimethylamino)-8-phenyl-1,3-diazaspiro[4.5-
]decan-2-one (INT-794) (3 g, 7.09 mmol) in DMSO (90 mL) under argon
atmosphere and the reaction mixture was stirred at 80.degree. C.
for 30 min. ((1-(Bromomethyl)cyclobutoxy)methyl)benzene (5.4 g,
21.3 mmol) was added and stirring was continued for 2 days at
80.degree. C. The reaction completion was monitored by TLC. The
reaction mixture was diluted with water (500 mL) and extracted with
diethyl ether (4.times.300 mL). The combined organic extracts were
dried over anhydrous Na.sub.2SO.sub.4 and concentrated under
reduced pressure. The residue was purified by column chromatography
(230-400 mesh silica gel; 65-70% EtOAc in petroleum ether as
eluent) to afford 2.5 g (59%) of
CIS-1-((1-(benzyloxy)cyclobutyl)methyl)-3-(3,4-dimethoxybenzyl)-8-(dimeth-
ylamino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one (TLC system: 10%
MeOH in DCM; Rf: 0.8).
Step 2:
CIS-8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-8-phenyl-1,3-
-diazaspiro[4.5]decan-2-one
[0195] TFA (12 mL) was added to
CIS-1-((1-(benzyloxy)cyclobutyl)methyl)-3-(3,4-dimethoxybenzyl)-8-(dimeth-
ylamino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one (2.5 g, 4.18 mmol)
at 0.degree. C. and the resulting mixture was stirred at 70.degree.
C. for 6 h. The reaction completion was monitored by LCMS. The
reaction mixture was concentrated under reduced pressure. To the
residue sat. aq. NaHCO.sub.3 was added (until pH 10) and the
organic product was extracted with DCM (3.times.150 mL). The
combined organic extracts were dried over anhydrous
Na.sub.2SO.sub.4 and concentrated under reduced pressure. The
residue was purified by column chromatography (230-400 mesh silica
gel; 5% MeOH in DCM as eluent) to afford 500 mg (33%) of
CIS-8-dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-8-phenyl-1,3-diazas-
piro[4.5]decan-2-one (INT-799) (TLC system: 10% MeOH in DCM; Rf:
0.5). [M+H].sup.+ 358.2
Synthesis of INT-897:
CIS-3-[1-(cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspir-
o[4.5]decan-3-yl]-2,2-dimethyl-propionic acid
##STR00019##
[0196] Step 1:
CIS-3-(1-(cyclobutylmethyl)-8-(dimethylamino)-2-oxo-8-phenyl-1,3-diazaspi-
ro[4.5]decan-3-yl)-2,2-dimethylpropanenitrile
[0197] KOtBu (1.7 g, 15.23 mmol) was added to a suspension of
CIS-1-(cyclobutyl-methyl)-8-dimethylamino-8-phenyl-1,3-diazaspiro[4.5]dec-
an-2-one (INT-987) (1.3 g, 3.80 mmol) in DMSO (20 mL) at RT.
3-Bromo-2,2-dimethylpropanenitrile (3.7 g, 28.81 mmol) was added
and the reaction mixture was stirred for 16 h at 130.degree. C. The
reaction mixture was quenched with cold water (25 mL) and the
organic product was extracted with EtOAc (2.times.20 mL). The
combined organic extracts were dried over anhydrous
Na.sub.2SO.sub.4 and concentrated under reduced pressure to give
1.6 g of
CIS-3-(1-(cyclobutylmethyl)-8-(dimethylamino)-2-oxo-8-phenyl-1,3-diazaspi-
ro[4.5]decan-3-yl)-2,2-dimethylpropanenitrile as a brown
semi-solid. (TLC system: 10% MeOH in DCM; Rf: 0.6). The product was
used in the next step without further purification.
Step 2:
CIS-3-[1-(cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-di-
azaspiro[4.5]decan-3-yl]-2,2-dimethyl-propionic acid
[0198] 12 N aq. HCl (16 mL) was added to
CIS-3-(1-(cyclobutylmethyl)-8-(dimethylamino)-2-oxo-8-phenyl-1,3-diazaspi-
ro[4.5]decan-3-yl)-2,2-dimethylpropanenitrile (1.6 g, 3.78 mmol)
and the resulting solution was refluxed for 16 h. The reaction
mixture was concentrated under reduced pressure. To the residue
toluene was added and the resulting mixture was concentrated under
reduced pressure again. The residue was washed with acetone (10
mL), diethyl ether (10 mL) and DCM (10 mL) to give 1.2 g of
CIS-3-[1-(cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspir-
o[4.5]decan-3-yl]-2,2-dimethyl-propionic acid (INT-897) as a solid.
(TLC system: 10% MeOH in DCM R.sub.f: 0.3.) [M+H].sup.+442.3
Synthesis of INT-898:
CIS-3-[1-(cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspir-
o[4.5]decan-3-yl]-propionic acid; 2,2,2-trifluoro-acetic acid
salt
##STR00020##
[0199] Step 1:
CIS-tert-butyl-3-(8-(dimethylamino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]dec-
an-3-yl)propanoate
[0200] KOtBu (1M in THF) (13.74 mL, 13.74 mmol) was added to a
solution of
CIS-1-(cyclobutyl-methyl)-8-dimethylamino-8-phenyl-1,3-diazaspiro[4.5]dec-
an-2-one (INT-987) (2.5 g, 9.16 mmol) in 1,4-dioxane (240 mL) under
argon atmosphere and the reaction mixture was stirred for 15
minutes. Tert-butyl acrylate (1.60 mL, 10.99 mmol) in 1,4-dioxane
(10 mL) was added. The reaction mixture was stirred for 1 h at RT,
then quenched with sat. aq. NH.sub.4Cl (60 mL) and the organic
product was extracted with EtOAc (2.times.100 mL). The combined
organic layer was dried over anhydr. Na.sub.2SO.sub.4 and
concentrated in vacuo. The crude product was purified by column
chromatography (using 100-200 mesh silica gel and 0-10 vol % MeOH
in DCM as eluent) to afford 1.2 g (32%) of tert-butyl
CIS-3-(8-(dimethylamino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)pro-
panoate as pale yellow solid (TLC system: 10% MeOH in DCM; Rf:
0.4).
Step 2:
CIS-3-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-di-
azaspiro[4.5]decan-3-yl]-propionic acid; 2,2,2-trifluoro-acetic
acid salt
[0201]
CIS-tert-butyl-3-(8-(dimethylamino)-2-oxo-8-phenyl-1,3-diazaspiro[4-
.5]decan-3-yl)propanoate (44 mg) was treated with TFA (360 .mu.L)
at RT for 30 min. All volatiles were removed in vacuo. The residue
was taken up in toluene and concentrated under reduced pressure
(3.times.) to yield
3-(cis-1-(cyclobutylmethyl)-8-(dimethylamino)-2-oxo-8-phenyl-1,3-diazaspi-
ro[4.5]decan-3-yl) propanoic acid as the trifluoroacetic acid salt
(INT-898) (54 mg). [M+H].sup.+ 414.3
Synthesis of INT-899:
CIS-3-[8-dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-2-oxo-8-phenyl-1-
,3-diazaspiro[4.5]decan-3-yl]-propionic acid
##STR00021##
[0202] Step 1: CIS-tert-butyl
3-(8-(dimethylamino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)propano-
ate
[0203] In analogy to the method described for INT-898 step 1
CIS-8-(dimethylamino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one
(INT-976) was converted into CIS-tert-butyl
3-(8-(dimethylamino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)propano-
ate.
Step 2:
CIS-3-[8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-2-oxo-8-p-
henyl-1,3-diazaspiro[4.5]decan-3-yl]-propionic acid
[0204] A mixture of CIS-tert-butyl
3-(8-(dimethylamino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)propano-
ate (2.2 g, 5.486 mmol) and powdered NaOH (877 mg, 21.95 mmol) in
toluene (40 mL) was stirred at 80.degree. C. for 5 h under argon
atmosphere. Toluene was evaporated in vacuo. The resulting
off-white solid was dissolved in DMSO (40 mL) under argon
atmosphere at RT and powdered NaOH (877 mg, 21.945 mmol) was added
in one portion. The reaction mixture was stirred at 55.degree. C.
for 1 h. (1-(tert-butyldimethylsilyloxy)cyclobutyl)methyl
4-methylbenzenesulfonate (2.029 g, 5.486 mmol) was added dropwise
over 5 min. The reaction mixture was stirred for 1.5 h at
55.degree. C. and a new portion of
(1-(tert-butyldimethylsilyloxy)cyclobutyl)methyl
4-methylbenzenesulfonate (2.029 g, 5.486 mmol) was added dropwise
over 5 min. Stirring was continued at 55.degree. C. for 18 h.
(1-(tert-butyldimethylsilyloxy)cyclobutyl)methyl
4-methylbenzenesulfonate (2.029 g, 5.486 mmol) was added dropwise
over 5 min and stirring was continued for 65 h at 55.degree. C. The
reaction progress was monitored by LCMS. DMSO was evaporated in
vacuo. The resulting crude product was dissolved in water (50 mL),
the solution was cooled to 0.degree. C. and neutralized with acetic
acid. The excess water was evaporated in vacuo and the residue was
purified by column chromatography (using 100-200 mesh silica gel
and 0-10 vol % MeOH in DCM as an eluent) to get 450 mg of
CIS-3-[8-dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-2-oxo-8-phenyl-1-
,3-diazaspiro[4.5]decan-3-yl]-propionic acid (INT-899) contaminated
with 4-methylbenzene-sulfonic acid (44% pure by LCMS) as a pale
yellow solid. This material was used for following reactions
without additional purification. [M+H].sup.+ 430.3
Synthesis of INT-951:
CIS-1-[(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-1-yl)-met-
hyl]-cyclobutane-1-carbonitrile
##STR00022##
[0205] Step 1:
1-((CIS-8-(dimethylamino)-3-(4-methoxybenzyl)-2-oxo-8-phenyl-1,3-diazaspi-
ro[4.5]decan-1-yl)methyl)cyclobutanecarbonitrile
[0206] NaH (50% in mineral oil) (2.44 g, 50.89 mmol) was added to a
solution of
CIS-8-dimethylamino-3-[(4-methoxyphenyl)-methyl]-8-phenyl-1,3-diazaspiro[-
4.5]decan-2-one (INT-975) (5 .mu.g, 12.72 mmol) in DMF (100 mL) at
0.degree. C. portionwise over 10 min.
1-(Bromomethyl)cyclobutanecarbonitrile (4.4 g, 25.44 mmol) was
added dropwise over 10 minutes at 0.degree. C. The reaction mixture
was allowed to stir at RT for 3 h, then quenched with water and the
organic product was extracted with ethyl acetate (3.times.200 mL).
The combined organic extracts were dried over anhydrous
Na.sub.2SO.sub.4 and concentrated under reduced pressure to afford
5 g (crude) of
1-((CIS-8-(dimethylamino)-3-(4-methoxybenzyl)-2-oxo-8-phenyl-1,3-diazaspi-
ro[4.5]decan-1-yl)methyl)cyclobutane-carbonitrile as gummy brown
liquid. The material was used for the next step without further
purification.
Step 2:
1-((CIS-8-(dimethylamino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan--
1-yl)methyl) cyclobutanecarboxamide
[0207] TFA (100 mL) was added to
1-((CIS-8-(dimethylamino)-3-(4-methoxybenzyl)-2-oxo-8-phenyl-1,3-diazaspi-
ro[4.5]decan-1-yl)methyl)cyclobutanecarbonitrile (5 g, 10.28 mmol)
at 0.degree. C. and the reaction mixture at mixture was stirred at
RT for 2 days. The reaction mixture was concentrated in vacuo. To
the residue sat. aq. NaHCO.sub.3 was added (until pH 10) and the
organic product was extracted with dichloromethane (3.times.150
mL). The combined organic extracts were dried over anhydrous
Na.sub.2SO.sub.4 and concentrated under reduced pressure to afford
3.5 g (crude) of
1-((CIS-8-(dimethylamino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-1-yl)me-
thyl) cyclobutanecarboxamide. The material was used for the next
step without further purification.
Step 3:
1-((cis-8-(dimethylamino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan--
1-yl)methyl)cyclobutane carbonitrile
[0208] Thionyl chloride (35 mL) was added to
1-((cis-8-(dimethylamino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-1-yl)me-
thyl)cyclobutanecarboxamide (3.5 g, 9.11 mmol) at RT and the
resulting mixture was stirred at reflux for 2 h. The reaction
mixture was concentrated in vacuo. To the residue sat. aq.
NaHCO.sub.3 was added (until pH 10) and the organic product was
extracted with dichloromethane (3.times.150 mL). The combined
organic layer was dried over anhydrous Na.sub.2SO.sub.4 and
concentrated in vacuo. The residue was purified by column
chromatography to afford 1.3 g (34% after three steps) of
CIS-1-[(8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-1-yl)-met-
hyl]-cyclobutane-1-carbonitrile (INT-951). [M+H].sup.+ 367.2.
Synthesis of INT-952:
CIS-1-(Cyclobutyl-methyl)-8-dimethylamino-8-phenyl-3-[(4-methoxyphenyl)-m-
ethyl]-1,3-diazaspiro[4.5]decan-2-one
##STR00023##
[0210] To a solution of
CIS-8-dimethylamino-3-[(4-methoxyphenyl)-methyl]-8-phenyl-1,3-diazaspiro[-
4.5]decan-2-one (INT-975) (10 g, 25 mmol) in THF (500 mL) was added
KOtBu (7.1 g, 63 mmol) at 50.degree. C. The reaction mixture was
heated up to reflux, cyclobutylmethylbromide (11.3 g, 76 mmol) was
added in one portion, and stirring was continued at reflux for 12
h. KOtBu (7.1 g) and cyclobutylmethylbromide (11.3 g) were added
again. The reaction mixture was allowed to stir another 2 h at
reflux, then cooled to RT, diluted with water (150 mL) and the
layers partitioned. The aqueous layer was extracted with EtOAc
(3.times.300 mL). The combined organic layers were dried over
Na.sub.2SO.sub.4 and then concentrated in vacuo. The residue was
filtered through a plug of silica gel using a DCM/MeOH (19/1 v/v)
mixture. The filtrate was concentrated in vacuo and the resulting
solid was recrystallized from hot ethanol to yield 7.8 g of
CIS-1-(cyclobutyl-methyl)-8-dimethylamino-8-phenyl-3-[(4-methoxyphenyl)-m-
ethyl]-1,3-diazaspiro[4.5]decan-2-one (INT-952). [M+H].sup.+
461.3.
Synthesis of INT-953:
CIS-1-(Cyclobutyl-methyl)-8-(methyl-(2-methyl-propyl)-amino)-8-phenyl-1,3-
-diazaspiro[4.5]decan-2-one
##STR00024##
[0211] Step 1:
1-Cyclobutylmethyl-3-(4-methoxy-benzyl)-9,12-dioxa-1,3-diaza-dispiro[4.2.-
4.2]tetradecan-2-one
[0212] To a stirred solution of
3-(4-methoxy-benzyl)-9,12-dioxa-1,3-diaza-dispiro[4.2.4.2]tetradecan-2-on-
e (4 g, 12.04 mmol) in anhydrous DMF (60 ml) was added NaH (1.38 g,
60% dispersion in oil, 36.14 mmol) at RT. The reaction mixture was
stirred for 10 min, bromomethylcyclobutane (3 ml, 26.5 mmol) was
added dropwise and stirring was continued for 50 h. TLC analysis
showed complete consumption of the starting material. The reaction
mixture was quenched with sat. aq. NH.sub.4Cl (50 ml) and extracted
with EtOAc (3.times.200 ml). The combined organic phase was dried
over Na.sub.2SO.sub.4 and concentrated under reduced pressure. The
resulting residue was purified column chromatography (neutral
aluminum oxide, EtOAc--petroleum ether (2:8)) to give
1-cyclobutylmethyl-3-(4-methoxy-benzyl)-9,12-dioxa-1,3-diaza-dispiro[4.2.-
4.2]tetradecan-2-one (2.4 g, 50%, white solid). TLC system:
EtOAc--pet ether (6:4); R.sub.f=0.48.
Step 2:
1-Cyclobutylmethyl-3-(4-methoxy-benzyl)-1,3-diaza-spiro[4.5]decane-
-2,8-dione
[0213] To a stirred solution of
1-cyclobutylmethyl-3-(4-methoxy-benzyl)-9,12-dioxa-1,3-diaza-dispiro[4.2.-
4.2]tetradecan-2-one (1 g, 2.5 mmol) in MeOH (7 ml) was added 10%
aq. HCl (8 ml) at 0.degree. C. The reaction mixture was warmed up
to RT and stirred for 16 h. TLC analysis showed complete
consumption of the starting material. The reaction mixture was
quenched with sat. aq. NaHCO.sub.3 (30 ml) and extracted with EtOAc
(3.times.50 ml). The combined organic phase was dried over
Na.sub.2SO.sub.4 and concentrated under reduced pressure. The
resulting residue was purified by column chromatography (silica
gel, 230-400 mesh, EtOAc--pet ether (1:3)-(3:7)) to give
1-cyclobutylmethyl-3-(4-methoxy-benzyl)-1,3-diaza-spiro[4.5]decan-
e-2,8-dione (650 mg, 73%, colorless viscous oil). TLC system:
EtOAc--pet ether (6:4); R.sub.f=0.40.
Step 3:
1-(cyclobutylmethyl)-8-(isobutyl(methyl)amino)-3-(4-methoxybenzyl)-
-2-oxo-1,3-diazaspiro[4.5]decane-8-carbonitrile
[0214] To a stirred solution of N-isobutyl-N-methylamine (1.34 ml,
11.23 mmol) and MeOH/H.sub.2O (8 ml, 1:1, v/v) was added 4N aq. HCl
(1.5 ml) and the reaction mixture was stirred for 10 min at
0.degree. C. (ice bath). A solution of
1-cyclobutylmethyl-3-(4-methoxy-benzyl)-1,3-diaza-spiro[4.5]decane-2,8-di-
one (1 g, 2.80 mmol) in MeOH (7 ml) and KCN (548 mg, 8.42 mmol)
were added and the reaction mixture was stirred at 45.degree. C.
for 20 h. TLC analysis showed complete consumption of the starting
material. The reaction mixture was diluted with water (30 ml),
extracted with EtOAc (3.times.30 ml), the combined organic phase
was dried over Na.sub.2SO.sub.4 and concentrated under reduced
pressure to give
1-(cyclobutylmethyl)-8-(isobutyl(methyl)amino)-3-(4-methoxybenzyl)-2-oxo--
1,3-diazaspiro[4.5]decane-8-carbonitrile (1.3 g, viscous yellow
oil). TLC system: EtOAc--pet ether (1:1); R.sub.f=0.45. The product
was used for the next step without additional purification.
Step 4:
CIS-1-(cyclobutylmethyl)-8-(isobutyl(methyl)amino)-3-(4-meth
oxybenzyl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one
[0215] A round bottom flask containing
1-(cyclobutylmethyl)-8-(isobutyl(methyl)amino)-3-(4-methoxybenzyl)-2-oxo--
1,3-diazaspiro[4.5]decane-8-carbonitrile (1.3 g, 2.81 mmol) was
cooled in an ice bath (.about.0.degree. C.) and a solution of
phenylmagnesium bromide (26 ml, .about.2M in THF) was added slowly
at 0.degree. C.-5.degree. C. The ice bath was removed and the
reaction mixture was stirred for 30 min, then diluted with sat. aq.
NH.sub.4Cl (25 ml) and extracted with EtOAc (4.times.30 ml). The
combined organic phase was dried over Na.sub.2SO.sub.4 and
concentrated under reduced pressure to give pale yellow viscous
oil. This residue was purified by column chromatography (silica
gel, 230-400 mesh, eluent: EtOAc--pet ether (15:85).fwdarw.(2:4))
to give
CIS-1-(cyclobutylmethyl)-8-(isobutyl(methyl)amino)-3-(4-methoxybenzyl)-8--
phenyl-1,3-diazaspiro[4.5]decan-2-one (135 mg, 10%, white solid).
TLC system: EtOAc--pet ether (1:1); R.sub.f=0.6
Step 5:
CIS-1-(Cyclobutyl-methyl)-8-(methyl-(2-methyl-propyl)-amino)-8-phe-
nyl-1,3-diazaspiro[4.5]decan-2-one
[0216] A round bottom flask containing
CIS-1-(cyclobutylmethyl)-8-(isobutyl(methyl)amino)-3-(4-methoxybenzyl)-8--
phenyl-1,3-diazaspiro[4.5]decan-2-one (130 mg, 0.25 mmol) was
cooled in an ice bath and a mixture of TFA/CH.sub.2Cl.sub.2 (2.6
ml, 1:1, v/v) was added slowly at 0.degree. C.-5.degree. C. The
reaction mixture was warmed to RT and stirred for 20 h, then
quenched with methanolic NH.sub.3 (10 ml, .about.10% in MeOH) and
concentrated under reduced pressure to give pale yellow viscous
oil. This residue was purified twice by column chromatography
(silica gel, 230-400 mesh, eluent: MeOH--CHCl.sub.3
(1:99).fwdarw.(2:98)) to give
CIS-1-(cyclobutyl-methyl)-8-(methyl-(2-methyl-propyl)-amino)-8-phenyl-1,3-
-diazaspiro[4.5]decan-2-one (INT-953) (65 mg, 66%, white solid).
TLC system: MeOH--CHCl.sub.3 (5:95); R.sub.f=0.25; [M+H].sup.+
384.3
Synthesis of INT-958:
4-Oxo-1-pyridin-2-yl-cyclohexane-1-carbonitrile
##STR00025##
[0217] Step 1: Ethyl
5-cyano-2-oxo-5-(pyridin-2-yl)cyclohexanecarboxylate
[0218] KOtBu (57.0 g, 508.4 mmol) was added to the solution of
2-(pyridin-2-yl)acetonitrile (50.0 g, 423.7 mmol) and ethyl
acrylate (89.0 g, 889.8 mmol) in THF (500 mL) at 0.degree. C. and
stirred for 16 h at RT. The reaction mixture was quenched with sat.
aq. NH.sub.4Cl and extracted with EtOAc (2.times.500 mL). The
combined organic layer was washed with brine, dried over
Na.sub.2SO.sub.4 and concentrated under reduced pressure to afford
68.0 g (60%; crude) of ethyl
5-cyano-2-oxo-5-(pyridin-2-yl)cyclohexanecarboxylate as a brown
liquid (TLC system: 50% ethyl acetate in petroleum ether; R.sub.f:
0.65).
Step 2: 4-Oxo-1-pyridin-2-yl-cyclohexane-1-carbonitrile
[0219] A solution of ethyl
5-cyano-2-oxo-5-(pyridin-2-yl)cyclohexanecarboxylate (68.0 g, 250.0
mmol) was added to a mixture of conc. aq. HCl and glacial acetic
acid (170 mL/510 mL) at 0.degree. C. The reaction mixture was
heated to 100.degree. C. for 16 h. All volatiles were evaporated
under reduced pressure. The residue was diluted with sat. aq.
NaHCO.sub.3 and extracted with ethyl acetate (3.times.300 mL). The
combined organic layer was washed with brine, dried over
Na.sub.2SO.sub.4 and concentrated under reduced pressure to afford
44.0 g (88%) of 4-oxo-1-pyridin-2-yl-cyclohexane-1-carbonitrile
INT-958 as a brown solid (TLC system: 50% ethyl acetate in pet
ether; R.sub.f: 0.45). [M+H].sup.+201.1
Synthesis of INT-961:
4-Dimethylamino-4-pyridin-2-yl-cyclohexan-1-one
##STR00026##
[0220] Step 1:
8-(pyridin-2-yl)-1,4-dioxaspiro[4.5]decane-8-carbonitrile
[0221] A solution of
4-oxo-1-pyridin-2-yl-cyclohexane-1-carbonitrile (INT-958) (44.0 g,
220.0 mmol), ethylene glycol (27.0 g, 440.0 mmol) and PTSA (4.2 g,
22.0 mmol) in toluene (450 mL) was heated to 120.degree. C. for 16
h using Dean Stark apparatus. All volatiles were evaporated under
reduced pressure. The residue was diluted with sat. aq. NaHCO.sub.3
and extracted with ethyl acetate (3.times.300 mL). The combined
organic layer was washed with brine, dried over Na.sub.2SO.sub.4
and concentrated under reduced pressure to afford 45.0 g (85%) of
8-(pyridin-2-yl)-1,4-dioxaspiro[4.5]decane-8-carbonitrile as a
light brown solid (TLC system: 50%0/ethyl acetate in petroleum
ether; R.sub.f: 0.55).
Step 2:
8-(pyridin-2-yl)-1,4-dioxaspiro[4.5]decane-8-carboxamide
[0222] Potassium carbonate (50.0 g, 368.84 mmol) and 30% aq.
H.sub.2O.sub.2 (210.0 mL, 1844.2 mmol) were added to the solution
of 8-(pyridin-2-yl)-1,4-dioxaspiro[4.5]decane-8-carbonitrile (45.0
g, 184.42 mmol) in DMSO (450 mL) at 0.degree. C. and the resulting
mixture was stirred at RT for 14 h. The reaction mixture was
diluted with water (1.5 L) and stirred for 1 h. The precipitated
solid was separated by filtration, washed with water, petroleum
ether and dried under reduced pressure to get 32.0 g (66%) of
8-(pyridin-2-yl)-1,4-dioxaspiro[4.5]decane-8-carboxamide as a white
solid. (TLC system: 10% MeOH in DCM R.sub.f: 0.35).
Step 3: methyl
8-(pyridin-2-yl)-1,4-dioxaspiro[4.5]decan-8-ylcarbamate
[0223] A mixture of
8-(pyridin-2-yl)-1,4-dioxaspiro[4.5]decane-8-carboxamide (25.0 g,
95.41 mmol), sodium hypochlorite (5 wt % aq. solution, 700 mL,
477.09 mmol) and KF--Al.sub.2O.sub.3 (125.0 g) in methanol (500 mL)
was heated to 80.degree. C. for 16 h. The reaction mixture was
filtered through celite and the solid residue was washed with
methanol. The combined filtrate was concentrated under reduced
pressure. The residue was diluted with water and extracted with
ethyl acetate (3.times.500 mL). The combined organic layer was
washed with brine, dried over Na.sub.2SO.sub.4 and concentrated
under reduced pressure to afford 18.0 g (66%) of methyl
8-(pyridin-2-yl)-1,4-dioxaspiro[4.5]decan-8-ylcarbamate as a light
brown solid. (TLC system: 5% MeOH in DCM R.sub.f: 0.52.)
Step 4: 8-(pyridin-2-yl)-1,4-dioxaspiro[4.5]decan-8-amine
[0224] A suspension of methyl
8-(pyridin-2-yl)-1,4-dioxaspiro[4.5]decan-8-ylcarbamate (18.0 g,
61.64 mmol) in 10 wt % aq. NaOH (200 mL) was heated to 100.degree.
C. for 24 h. The reaction mixture was filtered through celite pad,
the solid residue was washed with water and the combined filtrate
was extracted with EtOAc (4.times.200 mL). The combined organic
layer washed with brine, dried over Na.sub.2SO.sub.4 and
concentrated under reduced pressure to afford 12.5 g (88%) of
8-(pyridin-2-yl)-1,4-dioxaspiro[4.5]decan-8-amine as a light brown
semi-solid. (TLC system: 5% MeOH in DCM R.sub.f: 0.22.).
Step 5: 4-Dimethylamino-4-pyridin-2-yl-cyclohexan-1-one
[0225] Sodium cyanoborohydride (13.7 g, 0.213 mol) was added
portionwise to a solution of
8-(pyridin-2-yl)-1,4-dioxaspiro[4.5]decan-8-amine (12.5 g, 53.418
mmol) and 35 wt % aq. formaldehyde (45 mL, 0.534 mol) in
acetonitrile (130 mL) at 0.degree. C. The reaction mixture was
warmed up to room temperature and stirred for 16 h. The reaction
mixture was quenched with sat. aq. NH.sub.4Cl and concentrated
under reduced pressure. The residue was dissolved in water and
extracted with EtOAc (3.times.200 mL). The combined organic layer
was washed with brine, dried over Na.sub.2SO.sub.4 and concentrated
under reduced pressure to afford 10.5 g (72%) of
4-dimethylamino-4-pyridin-2-yl-cyclohexan-1-one (INT-961) as a
light brown solid. (TLC system: 5% MeOH in DCM R.sub.f: 0.32.).
[M+H].sup.+219.1
Synthesis of INT-965: 4-Dimethylamino-4-phenyl-cyclohexan-1-one
##STR00027##
[0226] Step 1:
8-(Dimethylamino)-1,4-dioxaspiro[4.5]decane-8-carbonitrile
[0227] Dimethylamine hydrochloride (52 g, 0.645 mol) was added to
the solution of 1,4-dioxaspiro-[4.5]-decan-8-one (35 g, 0.224 mmol)
in MeOH (35 mL) at RT under argon atmosphere. The solution was
stirred for 10 min and 40 wt % aq. dimethylamine (280 mL, 2.5 mol)
and KCN (32 g, 0.492 mol) were sequentially added. The reaction
mixture was stirred for 48 h at RT, then diluted with water (100
mL) and extracted with EtOAc (2.times.200 mL). The combined organic
layer was dried over anhydrous Na.sub.2SO.sub.4 and concentrated
under reduced pressure to afford 44 g of
8-(dimethylamino)-1,4-dioxaspiro-[4.5]-decane-8-carbonitrile (93%)
as a white solid.
Step 2: N,N-dimethyl-8-phenyl-1,4-dioxaspiro[4.5]decan-8-amine
[0228] 8-(Dimethylamino)-1,4-dioxaspiro[4.5]decane-8-carbonitrile
(35 g, 0.167 mol) in THF (350 mL) was added to the solution of 3M
phenylmagnesium bromide in diethyl ether (556 mL, 1.67 mol)
dropwise at -10.degree. C. under argon atmosphere. The reaction
mixture was stirred for 4 h at -10.degree. C. to 0.degree. C. and
then at RT for 18 h. The reaction completion was monitored by TLC.
The reaction mixture was cooled to 0.degree. C., diluted with sat.
aq. NH.sub.4Cl (1 L) and extracted with EtOAc (2.times.600 mL). The
combined organic layer was dried over anhydrous Na.sub.2SO.sub.4
and concentrated under reduced pressure to afford 60 g of, N
N-dimethyl-8-phenyl-1,4-dioxaspiro-[4.5]-decan-8-amine as a
liquid.
Step 3: 4-(dimethylamino)-4-phenylcyclohexanone
[0229] A solution of
N,N-dimethyl-8-phenyl-1,4-dioxaspiro[4.5]decan-8-amine (32 g, 0.123
mol) in 6N aq. HCl (320 mL) was stirred at 0.degree. C. for 2 h and
then at RT for 18 h. The reaction completion was monitored by TLC.
The reaction mixture was extracted with DCM (2.times.150 mL). The
aqueous layer was basified to pH 10 with solid NaOH and extracted
with ethyl acetate (2.times.200 mL). The combined organic layer was
dried over anhydrous Na.sub.2SO.sub.4 and concentrated under
reduced pressure. The solid residue was washed with hexane and
dried in vacuo to afford 7 g of
4-dimethylamino-4-phenyl-cyclohexan-1-one (INT-965) (25% over 2
steps) as a brown solid. [M+H].sup.+ 218.1
Synthesis of INT-966:
3-[(4-Methoxyphenyl)-methyl]-1,3-diazaspiro[4.5]decane-2,8-dione
##STR00028##
[0230] Step 1: 9,12-Dioxa-2,4-diazadispiro[4.2.4 {8}0.2
{5}]tetradecane-1,3-dione
[0231] KCN (93.8 g, 1441.6 mmol) and (NH.sub.4).sub.2CO.sub.3
(271.8 g, 1729.9 mmol) were added to the solution of
1,4-dioxaspiro[4.5]decan-8-one (150 g, 961 mmol) in MeOH:H.sub.2O
(1:1 v/v) (1.92 L) at RT under argon atmosphere. The reaction
mixture was stirred at 60.degree. C. for 16 h. The reaction
completion was monitored by TLC. The reaction mixture was cooled to
0.degree. C., the precipitated solid was filtered off and dried in
vacuo to afford 120 g (55%) of 9,12-dioxa-2,4-diazadispiro[4.2.4
{8}0.2{5}]tetradecane-1,3-dione. The filtrate was extracted with
DCM (2.times.1.5 L). The combined organic layer was dried over
anhydrous Na.sub.2SO.sub.4 and concentrated under reduced pressure
to afford additional 30 g (14%) of
9,12-dioxa-2,4-diazadispiro[4.2.4 {8}0.2 {5}]tetradecane-1,3-dione
(TLC system: 10% Methanol in DCM; Rf: 0.4).
Step 2:
2-[(4-Methoxyphenyl)-methyl]-9,12-dioxa-2,4-diazadispiro[4.2.4
{8}0.2 {5}]tetradecane-1,3-dione
[0232] Cs.sub.2CO.sub.3 (258.7 g, 796.1 mmol) was added to the
solution of 73a (150 g, 663.4 mmol) in MeCN (1.5 L) under argon
atmosphere and the reaction mixture was stirred for 30 min. A
solution of p-methoxybenzyl bromide (96 mL, 663.4 mmol) was added.
The reaction mixture was stirred at RT for 48 h. The reaction
completion was monitored by TLC. The reaction mixture was quenched
with sat. aq. NH.sub.4Cl (1.0 L) and the organic product was
extracted with EtOAc (2.times.1.5 L). The combined organic layer
was dried over anhydrous Na.sub.2SO.sub.4 and concentrated under
reduced pressure. The residue was washed with diethyl ether and
pentane and dried under reduced pressure to afford 151 g (65%) of
2-[(4-Methoxyphenyl)-methyl]-9,12-dioxa-2,4-diazadispiro[4.2.4{circumflex
over (.degree.)}{8}0.2{5}]tetradecane-1,3-dione as an off white
solid (TLC system: 10% MeOH in DCM; Rf: 0.6).
Step 3:
2-[(4-Methoxyphenyl)-methyl]-9,12-dioxa-2,4-diazadispiro[4.2.4
{8}.2 {5}]tetradecan-3-one
[0233] AlCl.sub.3 (144.3 g, 1082.6 mmol) was added to a solution of
LiAlH.sub.4 (2M in THF) (433 mL, 866.10 mmol) in THF (4.5 L) at
0.degree. C. under argon atmosphere and the resulting mixture was
stirred at RT for 1 h.
2-[(4-Methoxyphenyl)-methyl]-9,12-dioxa-2,4-diazadispiro[4.2.4
{8}0.2{5}]tetradecane-1,3-dione (150 g, 433.05 mmol) was added at
0.degree. C. The reaction mixture was stirred at RT for 16 h. The
reaction completion was monitored by TLC. The reaction mixture was
cooled to 0.degree. C., quenched with sat. aq. NaHCO.sub.3 (500 mL)
and filtered through celite pad. The filtrate was extracted with
EtOAc (2.times.2.0 L). The combined organic layer was dried over
anhydrous Na.sub.2SO.sub.4 and concentrated in vacuo to afford 120
g (84%) of
2-[(4-methoxyphenyl)-methyl]-9,12-dioxa-2,4-diazadispiro[4.2.4
{8}0.2 {5}]tetradecan-3-one as an off-white solid. (TLC system: 10%
MeOH in DCM, Rf: 0.5).
Step 4:
3-[(4-Methoxyphenyl)-methyl]-1,3-diazaspiro[4.5]decane-2,8-dione
[0234] A solution of
2-[(4-methoxyphenyl)-methyl]-9,12-dioxa-2,4-diazadispiro[4.2.4
{8}0.2 {5}]tetradecan-3-one (120 g, 361.03 mmol) in 6N aq. HCl (2.4
L) was stirred at 0.degree. C. for 2 h and then at RT for 18 h. The
reaction completion was monitored by TLC. The reaction mixture was
extracted with DCM (2.times.2.0 L). The aqueous layer was basified
to pH 10 with 50% aq. NaOH and then extracted with DCM (2.times.2.0
L). Combined organic extracts were dried over anhydrous
Na.sub.2SO.sub.4 and concentrated under reduced pressure. The solid
residue was washed with hexane and dried in vacuo to afford 90 g of
3-[(4-Methoxyphenyl)-methyl]-1,3-diazaspiro[4.5]decane-2,8-dione
(INT-966) as an off-white solid (TLC system: 10% MeOH in DCM; Rf:
0.4) [M+H].sup.+ 289.11.
Synthesis of INT-971:
CIS-1-(Cyclobutyl-methyl)-8-dimethylamino-8-(3-hydroxyphenyl)-3-[(4-metho-
xyphenyl)-methyl]-1,3-diazaspiro[4.5]decan-2-one
##STR00029##
[0236] Step 1:
CIS-8-(dimethylamino)-1-isobutyl-3-(4-methoxybenzyl)-8-phenyl-1,3-diazasp-
iro[4.5]decan-2-one
[0237] In analogy to the method described for INT-951 step 1
CIS-8-Dimethylamino-8-[3-(methoxymethyloxy)-phenyl]-3-[(4-methoxyphenyl)--
methyl]-1,3-diazaspiro[4.5]decan-2-one (INT-968) was converted into
CIS-1-(cyclobutylmethyl)-8-(dimethylamino)-3-(4-methoxybenzyl)-8-(3-(meth-
oxymethoxy)phenyl)-1,3-diazaspiro[4.5]decan-2-one.
Step 2:
CIS-1-(Cyclobutyl-methyl)-8-dimethylamino-8-(3-hydroxyphenyl)-3-[(-
4-methoxyphenyl)-methyl]-1,3-diazaspiro[4.5]decan-2-one
[0238] TFA (0.2 mL) was added to the solution of
CIS-1-(cyclobutylmethyl)-8-(dimethylamino)-3-(4-methoxybenzyl)-8-(3-metho-
xyphenyl)-1,3-diazaspiro[4.5]decan-2-one (300 mg, 0.57 mmol) in DCM
(1.5 mL) at 0.degree. C. The reaction mixture was stirred at
0.degree. C. for 3 h. The reaction completion was monitored by TLC.
The reaction mixture was quenched with sat. aq. NaHCO.sub.3 and the
organic product was extracted with DCM (3.times.10 mL). The
combined organic extracts were dried over anhydrous
Na.sub.2SO.sub.4 and concentrated under reduced pressure.
Purification of the residue by preparative TLC (3% MeOH in DCM as
mobile phase) yielded 50 mg (18%) of
CIS-1-(Cyclobutyl-methyl)-8-dimethylamino-8-(3-hydroxyphenyl)-3-[(4-metho-
xyphenyl)-methyl]-1,3-diazaspiro[4.5]decan-2-one (INT-971) as an
off white solid. (TLC system: 10% MeOH in DCM; Rf: 0.20)
[M+H].sup.+ 478.3
Synthesis of INT-974:
CIS-8-Dimethylamino-8-(3-fluorophenyl)-3-[(4-methoxyphenyl)-methyl]-1,3-d-
iazaspiro[4.5]decan-2-one
##STR00030##
[0239] Step 1:
8-(dimethylamino)-3-(4-methoxybenzyl)-2-oxo-1,3-diazaspiro[4.5]decane-8-c-
arbonitrile
[0240] Dimethylamine hydrochloride (76.4 g, 936.4 mmol) was added
to a solution of
3-[(4-methoxyphenyl)-methyl]-1,3-diazaspiro[4.5]decane-2,8-dione
(INT-966) (90 g, 312.13 mmol) in MeOH (180 mL) at RT under argon
atmosphere. The solution was stirred for 15 min and 40 wt % aq.
dimethylamine (780 mL) and KCN (48.76 g, 749.11 mmol) were
sequentially added. The reaction mixture was stirred for 48 h and
the completion of the reaction was monitored by NMR. The reaction
mixture was diluted with water (1.0 L) and the organic product was
extracted with ethyl acetate (2.times.2.0 L). The combined organic
layer was dried over anhydrous Na.sub.2SO.sub.4 and concentrated
under reduced pressure to afford 90 g (85%) of
8-(dimethylamino)-3-(4-methoxybenzyl)-2-oxo-1,3-diazaspiro[4.5]d-
ecane-8-carbonitrile as an off white solid (TLC system: TLC system:
10% MeOH in DCM; Rf: 0.35, 0.30).
Step 2: CIS-8-Dimethylamino-8-(3-fluorophenyl)-3-[(4-m
ethoxyphenyl)-methyl]-1,3-diazaspiro[4.5]decan-2-one
[0241] 3-Fluorophenylmagnesium bromide (1M in THF) (220 mL, 219.17
mmol) was added dropwise to a solution of
8-(dimethylamino)-3-(4-methoxybenzyl)-2-oxo-1,3-diazaspiro[4.5]decane-8-c-
arbonitrile (15 g, 43.83 mmol) in THF (300 mL) at 0.degree. C.
under argon atmosphere. The reaction mixture was stirred for 16 h
at RT. The reaction completion was monitored by TLC. The reaction
mixture was cooled to 0.degree. C., quenched with sat. aq.
NH.sub.4Cl (200 mL) and the organic product was extracted with
EtOAc (2.times.200 mL). The combined organic layer was dried over
anhydrous Na.sub.2SO.sub.4 and concentrated under reduced pressure.
The reaction was carried out in 4 batches (15 g.times.2 and 5
g.times.2) and the batches were combined for purification.
Purification of the crude product by flash column chromatography on
silica gel (230-400 mesh) (2 times) (0-20% methanol in DCM) eluent
and subsequently by washing with pentane yielded 5.6 g (11%) of
CIS-8-dimethylamino-8-(3-fluorophenyl)-3-[(4-methoxyphenyl)-methyl]-1,3-d-
iazaspiro[4.5]decan-2-one (INT-974) as an off-white solid. (TLC
system: 5% MeOH in DCM in presence of ammonia; Rf: 0.1).
[M+H].sup.+ 412.2
Synthesis of INT-975:
CIS-8-Dimethylamino-3-[(4-methoxyphenyl)-methyl]-8-phenyl-1,3-diazaspiro[-
4.5]decan-2-one
##STR00031##
[0243] KOtBu (1M in THF) (29.30 mL, 29.30 mmol) was added to the
solution of
CIS-8-Dimethylamino-8-phenyl-1,3-diazaspiro[4.5]decan-2-one INT-976
(8.0 g, 29.30 mmol) in THF (160 mL) under argon atmosphere and the
reaction mixture was stirred for 30 min. 4-Methoxybenzyl bromide
(4.23 mL, 29.30 mmol) was added and stirring was continued at RT
for 4 h. The reaction completion was monitored by TLC. The reaction
mixture was diluted with sat. aq. NH.sub.4Cl (150 mL) and the
organic product was extracted with EtOAc (2.times.150 mL). The
combined organic layer was dried over anhydrous Na.sub.2SO.sub.4
and concentrated in vacuo. The reaction was carried out in 2
batches (8 g.times.2) and the batches were combined for
purification. Purification of the crude product by flash column
chromatography on silica gel (0-10% methanol in DCM) and
subsequently by washing with pentane yielded 11 g (47%) of
CIS-8-Dimethylamino-3-[(4-methoxyphenyl)-methyl]-8-phenyl-1,3-diazaspiro[-
4.5]decan-2-one (INT-975) as a white solid. [M+H].sup.+ 394.2
Synthesis of INT-976:
CIS-8-Dimethylamino-8-phenyl-1,3-diazaspiro[4.5]decan-2-one
##STR00032##
[0244] Step 1:
8-(dimethylamino)-8-phenyl-1,3-diazaspiro[4,5]decane-2,4-dione
[0245] In a sealed tube 4-dimethylamino-4-phenyl-cyclohexan-1-one
(INT-965) (2 g, 9.22 mmol) was suspended in 40 mL EtOH/H.sub.2O
(1:1 v/v) at RT under argon atmosphere. (NH.sub.4).sub.2CO.sub.3
(3.62 g, 23.04 mmol) and KCN (0.6 g, 9.22 mmol) were added. The
reaction mixture was stirred at 60.degree. C. for 18 h. The
reaction mixture was cooled to 0.degree. C. and diluted with
ice-water and filtered through a glass filter. The solid residue
was dried under reduced pressure to afford
8-(dimethylamino)-8-phenyl-1,3-diazaspiro[4,5]decane-2,4-dione (1.8
g, 86%) as an off white crystalline solid (TLC: 80% EtOAc in
hexane; Rf: 0.25).
Step 2:
8-(dimethylamino)-8-phenyl-1,3-diazaspiro[4,5]decan-2-one
[0246] LiAlH.sub.4 (2M in THF) (70 mL, 139.4 mmol) was added to the
solution of
8-(dimethylamino)-8-phenyl-1,3-diazaspiro[4,5]decane-2,4-dione (10
g, 34.8 mmol) in THF/Et.sub.2O (2:1 v/v) (400 mL) at 0.degree. C.
under argon atmosphere. The reaction mixture was stirred for 4 h at
60.degree. C. The reaction completion was monitored by TLC. The
reaction mixture was cooled to 0.degree. C., quenched with
saturated Na.sub.2SO.sub.4 solution (100 mL) and filtered through
Celite pad. The filtrate was dried over anhydrous Na.sub.2SO.sub.4
and concentrated in vacuo to afford 5.7 g (59%) of
8-(dimethylamino)-8-phenyl-1,3-diazaspiro[4,5]decan-2-one as an off
white solid. (TLC system: 10% MeOH in DCM, Rf: 0.3).
Step 3:
CIS-8-Dimethylamino-8-phenyl-1,3-diazaspiro[4.5]decan-2-one
[0247] A mixture of CIS- and
TRANS-8-(dimethylamino)-8-phenyl-1,3-diazaspiro[4,5]decan-2-one (8
g, 29.30 mmol) was purified by preparative chiral SFC (column:
Chiralcel AS-H, 60% CO.sub.2, 40% (0.5% DEA in MeOH)) to get 5 g of
CIS-8-Dimethylamino-8-phenyl-1,3-diazaspiro[4.5]decan-2-one
(INT-976) as a white solid. [M+H].sup.+ 274.2.
Synthesis of INT-977:
CIS-2-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-1-yl)-acet-
ic acid; 2,2,2-trifluoro-acetic acid salt
##STR00033##
[0248] Step 1:
CIS-2-[8-Dimethylamino-3-[(4-methoxyphenyl)-methyl]-2-oxo-8-phenyl-1,3-di-
azaspiro[4.5]decan-1-yl]-acetic acid tert-butyl ester
[0249] A solution of
CIS-8-Dimethylamino-3-[(4-methoxyphenyl)-methyl]-8-phenyl-1,3-diazaspiro[-
4.5]decan-2-one (INT-975) (5.0 g, 12.7 mmol) in THF (18 mL) was
cooled to 0.degree. C. and treated with LDA solution (2M in
THF/heptane/ether, 25.4 mL, 50.8 mmol). The resulting mixture was
allowed to warm up to RT over 30 min. The solution was then cooled
to 0.degree. C. again and tert-butyl-bromoacetate (5.63 mL, 38.1
mmol) was added. The reaction mixture was stirred at RT for 16 h,
quenched with water and extracted with DCM (3.times.). The combined
organic layers were dried over Na.sub.2SO.sub.4, filtered and
concentrated under reduced pressure. Purification of the residue by
column chromatography on silica gel provided
CIS-2-[8-dimethylamino-3-[(4-methoxyphenyl)-methyl]-2-oxo-8-phen-
yl-1,3-diazaspiro[4.5]decan-1-yl]-acetic acid tert-butyl ester (4.4
g).
Step 2:
cis-2-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-1-y-
l)-acetic acid trifluoroacetic acid salt
[0250]
CIS-2-[8-Dimethylamino-3-[(4-methoxyphenyl)-methyl]-2-oxo-8-phenyl--
1,3-diazaspiro[4.5]decan-1-yl]-acetic acid tert-butyl ester (200
mg, 0.4 mmol) was dissolved in TFA (5 mL) and heated to reflux
overnight. After cooling to RT all volatiles are removed in vacuo.
The residue was taken up in THF (1 mL) and added dropwise to
diethyl ether (20 mL). The resulting precipitate was filtered off
and dried under reduced pressure to give
CIS-2-(8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-1--
yl)-acetic acid; 2,2,2-trifluoro-acetic acid salt (INT-977) (119
mg) as a white solid. [M+H].sup.+ 332.2
Synthesis of INT-978:
CIS-2-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-1-yl)-N,N--
dimethyl-acetamide
##STR00034##
[0252]
CIS-2-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-1-yl-
)-acetic acid (INT-977) trifluoroacetic acid salt (119 mg, 0.35
mmol) was dissolved in DCM (5 mL). Triethylamine (0.21 mL, 1.6
mmol), dimethylamine (0.54 mL, 1.1 mmol) and T3P (0.63 mL, 1.1
mmol) were sequentially added. The reaction mixture was stirred at
RT overnight, then diluted with 1 M aq. Na.sub.2CO.sub.3 (5 mL).
The aqueous layer was extracted with DCM (3.times.5 mL), the
combined organic layers were dried over Na.sub.2SO.sub.4 and
concentrated under reduced pressure. The residue was purified by
flash chromatography on silica gel to yield
CIS-2-(8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-1-yl)-N,N--
dimethyl-acetamide (INT-978) (39 mg) as a white solid. [M+H].sup.+
359.2
Synthesis of INT-982:
CIS-8-Dimethylamino-1-[(1-methyl-cyclobutyl)-methyl]-8-phenyl-1,3-diazasp-
iro[4.5]decan-2-one
##STR00035##
[0253] Step 1:
CIS-8-(dimethylamino)-3-(4-methoxybenzyl)-1-((1-methylcyclobutyl)methyl)--
8-phenyl-1,3-diazaspiro[4.5]decan-2-one
[0254] A solution of NaOH (2.85 g, 71.2 mmol) in DMSO (25 mL) was
stirred at RT for 10 min.
CIS-8-Dimethylamino-3-[(4-methoxyphenyl)-methyl]-8-phenyl-1,3-diazaspiro[-
4.5]decan-2-one (INT-975) (7.00 g, 17.8 mmol) was added and
stirring was continued for 15 min.
1-(Bromomethyl)-1-methyl-cyclobutane (8.7 g, 53.4 mmol) was added
at 0.degree. C. The reaction mixture was heated to 60.degree. C.
for 16 h. After cooling down to RT, water (100 mL) was added and
the mixture was extracted with DCM (3.times.150 mL). The combined
organic layers were washed with water (70 mL), brine (100 mL),
dried over Na.sub.2SO.sub.4 and concentrated under reduced
pressure. Purification of the residue by column chromatography on
silica gel provided
CIS-8-(dimethylamino)-3-(4-methoxybenzyl)-1-((1-methylcyclobutyl-
)methyl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one (6.5 g) as a light
yellow solid.
Step 2:
CIS-8-Dimethylamino-1-[(1-methyl-cyclobutyl)-methyl]-8-phenyl-1,3--
diazaspiro[4.5]decan-2-one
[0255] To the solution of
CIS-8-Dimethylamino-1-[(1-methyl-cyclobutyl)-methyl]-8-phenyl-1,3-diazasp-
iro[4.5]decan-2-one (6.66 g, 14.0 mmol) in DCM (65 mL) was added
TFA (65 mL) and the resulting mixture was stirred at RT for 16 h.
The reaction mixture was concentrated under reduced pressure. The
residue was taken up in DCM (100 mL) and water (60 mL) and basified
with 2M aq. NaOH to pH 10. The organic layer was separated and
washed with brine (40 mL), dried over MgSO.sub.4, filtered and
concentrated under reduced pressure. Crystallization of the residue
from EtOAc provided
CIS-8-Dimethylamino-1-[(1-methyl-cyclobutyl)-methyl]-8-phenyl-1,3-diazasp-
iro[4.5]decan-2-one (INT-982) (3.41 g) as an off-white solid.
[M+H].sup.+ 356.3
Synthesis of INT-984:
CIS-1-(Cyclobutyl-methyl)-8-(ethyl-methyl-amino)-8-phenyl-1,3-diazaspiro[-
4.5]decan-2-one
##STR00036##
[0256] Step 1:
CIS-8-(dimethylamino)-1-isobutyl-3-(4-methoxybenzyl)-8-phenyl-1,3-diazasp-
iro[4.5]decan-2-one
[0257] In analogy to the method described for INT-951 step 1
CIS-8-Dimethylamino-3-[(4-methoxyphenyl)-methyl]-8-phenyl-1,3-diazaspiro[-
4.5]decan-2-one (INT-975) was converted into
CIS-8-(dimethylamino)-l-isobutyl-3-(4-methoxybenzyl)-8-phenyl-1,3-diazasp-
iro[4.5]decan-2-one.
Step 2:
CIS-1-(Cyclobutyl-methyl)-8-(ethyl-methyl-amino)-8-phenyl-1,3-diaz-
aspiro[4.5]decan-2-one
[0258] In analogy to the method described for INT-982 step 2
CIS-8-(dimethylamino)-1-isobutyl-3-(4-methoxybenzyl)-8-phenyl-1,3-diazasp-
iro[4.5]decan-2-one was converted into
CIS-1-(Cyclobutyl-methyl)-8-(ethyl-methyl-amino)-8-phenyl-1,3-diazaspiro[-
4.5]decan-2-one (INT-984).
Synthesis of INT-986:
CIS-1-(Cyclobutyl-methyl)-8-(ethyl-methyl-amino)-8-phenyl-1,3-diazaspiro[-
4.5]decan-2-one
##STR00037##
[0259] Step 1:
CIS-3-benzyl-1-(cyclobutylmethyl)-8-(methylamino)-8-phenyl-1,3-diazaspiro-
[4.5]decan-2-on e
[0260] N-Iodosuccinimide (3.11 g, 13.92 mmol) was added to the
solution of
CIS-1-(Cyclobutyl-methyl)-8-dimethylamino-8-phenyl-3-[phenyl-methyl]-1,3--
diazaspiro[4.5]decan-2-one (INT-950) (4 g, 9.28 mmol) in a mixture
of acetonitrile and THF (1:1 v/v, 80 mL) and the resulting mixture
was stirred at RT for 16 h. The reaction mixture was basified with
2N aq. NaOH to pH-10 and the organic product was extracted with DCM
(3.times.10 mL). The combined organic extracts were dried over
anhydrous Na.sub.2SO.sub.4 and concentrated in vacuo. The residue
was stirred vigorously with a mixture of 10 wt % aq. citric acid (5
mL) and DCM (10 mL) at RT for 10 min. The reaction mixture was
basified with 5N aq. NaOH to pH-10 and extracted with DCM
(3.times.10 mL). The combined organic layer was dried over
anhydrous Na.sub.2SO.sub.4 and concentrated in vacuo to give 3.5 g
(crude) of
CIS-3-benzyl-1-(cyclobutylmethyl)-8-(methylamino)-8-phenyl-1,3-diazaspiro-
[4.5]decan-2-one as semi solid (TLC system: 10% MeOH in DCM;
R.sub.f: 0.60.).
Step 2:
CIS-3-benzyl-1-(cyclobutylmethyl)-8-(ethyl(methyl)amino)-8-phenyl--
1,3-diazaspiro[4.5]decan-2-one
[0261] Sodium cyanoborohydride (1.56 g, 25.17 mmol, 3 equiv.) was
added to the solution of
CIS-3-benzyl-1-(cyclobutylmethyl)-8-(methylamino)-8-phenyl-1,3-diazaspiro-
[4.5]decan-2-one (3.5 g, 8.39 mmol), acetaldehyde (738 mg, 16.78
mmol, 2 equiv.) and acetic acid (0.5 mL) in methanol (20 mL). The
reaction mixture was stirred at RT for 3 h, then quenched with sat.
aq. NaHCO.sub.3 and the organic product was extracted with DCM
(3.times.50 mL). The combined organic extracts were dried over
anhydrous Na.sub.2SO.sub.4 and concentrated in vacuo. Purification
of the residue by flash column chromatography on silica gel
(230-400 mesh) (20-25% ethyl acetate in petroleum ether) yielded
2.3 g (62%) of
CIS-3-benzyl-1-(cyclobutylmethyl)-8-(ethyl(methyl)amino)-8-phenyl-1,3-dia-
zaspiro[4.5]decan-2-one as a solid. (TLC system: 50% EtOAc in Pet.
Ether; R.sub.f: 0.65).
Step 3:
CIS-1-(Cyclobutyl-methyl)-8-(ethyl-methyl-amino)-8-phenyl-1,3-diaz-
aspiro[4.5]decan-2-one (INT-986)
[0262] Sodium metal (1.18 g, 51.68 mmol, 10 equiv.) was added to
liquid ammonia (25 mL) at -78.degree. C. The resulting mixture was
stirred for 10 min at -78.degree. C. A solution of
CIS-3-benzyl-1-(cyclobutylmethyl)-8-(ethyl(methyl)amino)-8-phenyl-1,3-dia-
zaspiro[4.5]decan-2-one (2.3 g, 5.16 mmol) in THF (25 mL) was added
at -78.degree. C. The reaction mixture was stirred for 15 min, then
quenched with sat. aq. NH.sub.4Cl, warmed to RT and stirred for 1
h. The organic product was extracted with DCM (3.times.50 mL). The
combined organic layer was washed with water, brine and
concentrated under reduced pressure to afford 1.30 g (72%) of
CIS-1-(cyclobutylmethyl)-8-(ethyl(methyl)amino)-8-phenyl-1,3-diazaspiro[4-
.5]decan-2-one (INT-986) as an off-white solid. (TLC system: 10%
MeOH in DCM R.sub.f: 0.15.). [M+H].sup.+ 356.3
Synthesis of INT-987:
CIS-1-(Cyclobutyl-methyl)-8-dimethylamino-8-phenyl-1,3-diazaspiro[4.5]dec-
an-2-one
##STR00038##
[0264] In analogy to the method as described for INT-982 step 2
CIS-1-(Cyclobutyl-methyl)-8-dimethylamino-8-phenyl-3-[(4-methoxyphenyl)-m-
ethyl]-1,3-diazaspiro[4.5]decan-2-one (INT-952) was converted into
CIS-1-(Cyclobutyl-methyl)-8-dimethylamino-8-phenyl-1,3-diazaspiro[4.5]dec-
an-2-one (INT-987).
Synthesis of INT-1008:
CIS-8-ethylamino-8-phenyl-1,3-diaza-spiro[4.5]decan-2-one
##STR00039##
[0265] Step 1 and step 2:
ethyl-(8-phenyl-1,4-dioxa-spiro[4.5]dec-8-yl)-amine hydrochloride
(INT-1004)
[0266] A mixture of 1,4-dioxa-spiro[4.5]decan-8-one (25.0 g, 160.25
mmol, 1.0 eq.) and 2M solution of EtNH.sub.2 in THF (200 ml, 2.5
eq. 400.64 mmol) in EtOH (30 mL) was stirred at RT for 48 h. The
reaction mixture was concentrated under argon atmosphere. The
residue was diluted with ether (60 mL) and added to the freshly
prepared PhLi solution [prepared by addition of 2.5M n-BuLi in THF
(70.5 mL, 1.1 eq. 176.27 mmol) to a solution of bromobenzene
(27.675 g, 1.1 eq. 176.275 mmol) in ether (100 mL) at -30.degree.
C. and stirred at RT for 1 h] at RT. The reaction mixture was
stirred at RT for 1.5 h, then cooled down to 0.degree. C. and
quenched with sat. aq. NH.sub.4Cl (100 mL). The resulting mixture
was extracted with EtOAc (2.times.750 mL), combined organic
extracts were washed with water (3.times.350 mL), brine (300 mL),
dried over Na.sub.2SO.sub.4 and concentrated under reduced
pressure. The crude product was dissolved in ethylmethyl ketone
(100 mL) and TMSCl (37.5 mL) was added at 0.degree. C. The reaction
mixture was stirred at RT for 16 h, the precipitate formed was
filtered off and washed with acetone and THF to give
ethyl-(8-phenyl-1,4-dioxa-spiro[4.5]dec-8-yl)-amine hydrochloride
as an off-white solid. This reaction was done in 2 batches of 25 g
scale and the yield is given for 2 combined batches. Yield: 18%
(17.1 g, 57.575 mmol). LCMS: m/z 262.2 (M+H)+.
Step 3: 4-ethylamino-4-phenyl-cyclohexanone (INT-1005)
[0267] To a solution of
ethyl-(8-phenyl-1,4-dioxa-spiro[4.5]dec-8-yl)-amine hydrochloride
(10.1 g, 34.0 mmol, 1 eq.) in water (37.5 mL) was added conc. HCl
(62.5 mL) at 0.degree. C. and the reaction mixture was stirred at
RT for 16 h. The reaction mixture was basified with 1N aq. NaOH to
pH .about.14 at 0.degree. C. and extracted with DCM (2.times.750
mL). Organic layer was washed with water (400 mL), brine (400 mL),
dried over Na.sub.2SO.sub.4 and concentrated under reduced pressure
to yield 4-ethylamino-4-phenyl-cyclohexanone which was used in the
next step without further purification. This reaction was carried
out in another batch of 15.1 g scale and yield is given for 2
combined batches. Yield: 92% (17.0 g, 78.34 mmol).
Step 4: mixture of CIS- and
TRANS-8-ethylamino-8-phenyl-1,3-diaza-spiro[4.5]decane-2,4-dione
(INT-1006 and INT-1007)
[0268] To a solution of 4-ethylamino-4-phenyl-cyclohexanone (17 g,
78.341 mmol, 1.0 eq.) in EtOH (250 mL) and water (200 mL) was added
(NH.sub.4).sub.2CO.sub.3 (18.8 g, 195.85 mmol, 2.5 eq.) and the
reaction mixture was stirred at RT for 15 min. KCN (5.09 g, 78.341
mmol, 1.0 eq.) was and the resulting mixture was stirred at
60.degree. C. for 18 h. The reaction mixture was cooled to RT, the
precipitate was filtered off, washed with water (250 mL), EtOH (300
mL), hexane (200 mL) and dried under reduced pressure to yield CIS-
and TRANS-mixture
8-ethylamino-8-phenyl-1,3-diaza-spiro[4.5]decane-2,4-dione (13.0 g,
45.29 mmol, 58%) as a white solid. Yield: 58% (13 g, 45.296 mmol).
LC-MS: m/z [M+1].sup.+=288.2.
Step 5:
CIS-8-ethylamino-8-phenyl-1,3-diaza-spiro[4.5]decane-2,4-dione
(INT-1006)
[0269] To a solution of cis and trans mixture of
8-ethylamino-8-phenyl-1,3-diaza-spiro[4.5]decane-2,4-dione (12 g)
in MeOH/DCM (1:1 v/v, 960 mL) was added a solution of L-tartaric
acid in MeOH (25 mL). The resulting mixture was stirred at RT for 2
h and then kept in refrigerator for 16 h. The solid material was
filtered off and washed with MeOH/DCM (1:5, 50 ml) to get
8-ethylamino-8-phenyl-1,3-diaza-spiro[4.5]decane-2,4-dione tartrate
(7.5 g) as a white solid. The solid was suspended in sat. aq.
NaHCO.sub.3 (pH-8) and the resulting mixture was extracted with 25%
MeOH-DCM (2.times.800 ml). Combined organic extracts were washed
with water (300 ml), brine (300 ml) and dried over anhydrous
Na.sub.2SO.sub.4. The solvent was evaporated under reduced pressure
and the residue was triturated with 20% DCM-hexane to afford
CIS-8-ethylamino-8-phenyl-1,3-diaza-spiro[4.5]decane-2,4-dione as a
white solid. This step was done in 2 batches (12 g & 2.4 g) and
yield is given for 2 combined batches. Yield: 31.2% (5.0 g, 17.421
mmol). LC-MS: m/z [M+1].sup.+=288.0.
Step 6: CIS-8-ethylamino-8-phenyl-1,3-diaza-spiro[4.5]decan-2-one
(INT-1008)
[0270] To a slurry of LiAlH.sub.4 (793 mg, 20.905 mmol, 3.0 eq.) in
THF (15 mL) was added a suspension of
cis-8-ethylamino-8-phenyl-1,3-diaza-spiro[4.5]decane-2,4-dione (2.0
g, 6.968 mmol, 1.0 eq.) in THF (60 mL) at 0.degree. C. and the
reaction mixture was stirred at 65.degree. C. for 16 h. The
resulting mixture was cooled to 0.degree. C., quenched with sat.
aq. Na.sub.2SO.sub.4 (20 ml), stirred at RT for 1 h and filtered
through celite. The celite layer was washed with 15% MeOH-DCM (500
ml). The combined filtrate was dried over anhydrous
Na.sub.2SO.sub.4 and concentrated under reduced pressure. The
resulting crude product was triturated with 15% DCM-Hexane to
afford CIS-8-ethylamino-8-phenyl-1,3-diaza-spiro[4.5]decan-2-one
(INT-1008) (1.6 g, 5.86 mmol, 84%) as a white solid. Yield: 84%
(1.6 g, 5.86 mmol). LC-MS: m/z [M+H].sup.+=274.2.
Synthesis of INT-1026:
CIS-8-(methyl((tetrahydrofuran-3-yl)methyl)amino)-8-phenyl-1,3-diazaspiro-
[4.5]decan-2-one
##STR00040##
[0271] Step 1:
2-methyl-N-(1,4-dioxaspiro[4.5]decan-8-ylidene)propane-2-sulfinamide
[0272] Titanium ethoxide (58.45 g, 256.4 mmol) was added to a
solution of 1,4-dioxaspiro[4.5]decan-8-one (20 g, 128.20 mmol) and
2-methylpropane-2-sulfinamide (15.51 g, 128.20 mmol) in THF (200
mL) at RT and the reaction mixture was stirred at RT for 18 h. The
reaction mixture was cooled to 0.degree. C. and quenched by
dropwise addition of sat. aq. NaHCO.sub.3 (500 mL) over a period of
30 min. The organic product was extracted with EtOAc (3.times.100
mL). The combined organic extracts were dried over anhydrous
Na.sub.2SO.sub.4 and concentrated in vacuo to afford 10 g (crude)
of
2-methyl-N-(1,4-dioxaspiro[4.5]decan-8-ylidene)propane-2-sulfinamide
as a white solid (TLC system: 30% Ethyl acetate in hexane; Rf:
0.30).
Step 2:
2-methyl-N-(8-phenyl-1,4-dioxaspiro[4.5]decan-8-yl)propane-2-sulfi-
namide
[0273] Phenylmagnesium bromide (1M in THF, 116 mL, 116 mmol) was
added dropwise to a solution of
2-methyl-N-(1,4-dioxaspiro[4.5]decan-8-ylidene)propane-2-sulfinamide
(10 g, 38.61 mmol) in THF (500 mL) at -10.degree. C. under argon
atmosphere. The reaction mixture was stirred for 2 h at -10.degree.
C. to 0.degree. C. The reaction completion was monitored by TLC.
The reaction mixture was quenched with sat. aq. NH.sub.4Cl (50 mL)
at 0.degree. C. and the organic product was extracted with EtOAc
(3.times.100 mL). The combined organic extracts were dried over
anhydrous Na.sub.2SO.sub.4 and concentrated in vacuo. The residue
was purified by column chromatography (silica gel 230-400 mesh;
40-60% ethyl acetate in hexane) to yield 6.0 g (46%) of
2-methyl-N-(8-phenyl-1,4-dioxaspiro[4.5]decan-8-yl)propane-2-sulfinamide
as a liquid (TLC system: 70% Ethyl acetate in hexane; Rf:
0.30).
Step 3: 8-phenyl-1,4-dioxaspiro[4.5]decan-8-amine hydrochloride
[0274] 2N solution of HCl in diethyl ether (17.80 mL, 35.60 mmol)
was added to a solution of
2-methyl-N-(8-phenyl-1,4-dioxaspiro[4.5]decan-8-yl)propane-2-sulfinamide
(6.0 g, 17.80 mmol) in DCM (60 mL) at 0.degree. C. The reaction
mixture was stirred at RT for 2 h. The reaction mixture was
concentrated in vacuo. The residue was washed with diethyl ether to
yield 3 g (crude) of 8-phenyl-1,4-dioxaspiro[4.5]decan-8-amine
hydrochloride as a brown solid (TLC system: 5% MeOH in DCM; Rf:
0.10).
Step 4:
8-phenyl-N-((tetrahydrofuran-3-yl)methyl)-1,4-dioxaspiro[4.5]decan-
-8-amine
[0275] Sodium cyanoborohydride (2.17 g, 33.45 mmol) was added to a
solution of 8-phenyl-1,4-dioxaspiro[4.5]decan-8-amine hydrochloride
(3.0 g, 11.15 mmol) and tetrahydrofuran-3-carbaldehyde (4.46 mL,
22.30 mmol) and acetic acid (0.05 mL) in methanol (30 mL) at
0.degree. C. The reaction mixture was stirred at RT for 16 h. The
reaction mixture was concentrated in vacuo at 30.degree. C. and to
the residue sat. aq. NaHCO.sub.3 was added. The organic product was
extracted with DCM (3.times.30 mL). The combined organic extracts
were dried over anhydrous Na.sub.2SO.sub.4 and solvent was
concentrated under reduced pressure to get 3 g (crude) of
8-phenyl-N-((tetrahydrofuran-3-yl)methyl)-1,4-dioxaspiro[4.5]decan-8-amin-
e as a semi-solid (TLC system: 10% MeOH in DCM; Rf: 0.22).
Step 5:
N-methyl-8-phenyl-N-((tetrahydrofuran-3-yl)methyl)-1,4-dioxaspiro[-
4.5]decan-8-amine)
[0276] Sodium cyanoborohydride (1.76 g, 28.39 mmol) was added to a
solution of
8-phenyl-N-((tetrahydrofuran-3-yl)methyl)-1,4-dioxaspiro[4.5]decan-8-amin-
e (3.0 g, 9.46 mmol), 37% formaldehyde in water (7.70 mL, 94.60
mmol) and acetic acid (0.05 mL) in methanol (30 mL) at 0.degree. C.
The reaction mixture was stirred at RT for 16 h. The reaction
mixture was concentrated in vacuo and to the residue sat. aq.
NaHCO.sub.3 was added. The organic product was extracted with DCM
(3.times.30 mL). The combined organic extracts were dried over
anhydrous Na.sub.2SO.sub.4 and solvent was concentrated under
reduced pressure. The resulting residue was purified by column
chromatography (silica gel 230-400 mesh; 5-6% MeOH in DCM) to yield
2.50 g (83%) of
N-methyl-8-phenyl-N-((tetrahydrofuran-3-yl)methyl)-1,4-dioxaspiro[4.5]dec-
an-8-amine as a semi solid (TLC system: 10% MeOH in DCM; Rf:
0.25).
Step 6:
4-(methyl((tetrahydrofuran-3-yl)methyl)amino)-4-phenylcyclohexanon-
e
[0277] 5% sulfuric acid in water (25 mL) was added to
N-methyl-8-phenyl-N-((tetrahydrofuran-3-yl)methyl)-1,4-dioxaspiro[4.5]dec-
an-8-amine (2.50 g, 7.55 mmol) at 0.degree. C. and the resulting
mixture was stirred at RT for 24 h. The reaction mixture was
quenched with sat. aq. NaHCO.sub.3 and the organic product was
extracted with DCM (2.times.50 mL). The combined organic layers
were dried over anhydrous Na.sub.2SO.sub.4 and concentrated in
vacuo to afford 2.0 g (crude) of
4-(methyl((tetrahydrofuran-3-yl)methyl)amino)-4-phenylcyclohexanone
as a thick liquid (TLC system: 10% MeOH in DCM, Rf: 0.20).
Step 7:
8-(methyl((tetrahydrofuran-3-yl)methyl)amino)-8-phenyl-1,3-diazasp-
iro[4.5]decane-2,4-dione
[0278]
4-(methyl((tetrahydrofuran-3-yl)methyl)amino)-4-phenylcyclohexanone
(1.50 g, 5.22 mmol) was suspended in 30 mL of EtOH:H.sub.2O (1:1
v/v) at RT under argon atmosphere. (NH.sub.4).sub.2CO.sub.3 (1.9 g,
13.05 mmol) and KCN (0.34 g, 5.22 mmol) were added. The reaction
mixture was heated to 70.degree. C. for 16 h. The reaction mixture
was diluted with ice-water and the organic product was extracted
with DCM (2.times.50 mL). The combined organic layer was dried over
anhydrous Na.sub.2SO.sub.4 and concentrated in vacuo to give 1.0 g
(crude) of
8-(methyl((tetrahydrofuran-3-yl)methyl)amino)-8-phenyl-1,3-diazaspiro[4.5-
]decane-2,4-dione as a solid (TLC system: 70% Ethyl acetate in
hexane; Rf: 0.18).
Step 8: CIS-8-(methyl((tetrahydrofuran-3-yl)meth
yl)amino)-8-phenyl-1,3-diazaspiro[4.5]decane-2,4-dione
[0279] Diastereomeric mixture of
8-(methyl((tetrahydrofuran-3-yl)methyl)amino)-8-phenyl-1,3-diazaspiro[4.5-
]decane-2,4-dione (1.0 g) was separated by reverse phase
preparative HPLC to afford 400 mg of isomer 1
(CIS-8-(methyl((tetrahydrofuran-3-yl)methyl)amino)-8-phenyl-1,3-diazaspir-
o[4.5]decane-2,4-dione) and 60 mg of isomer 2
(TRANS-8-(methyl((tetrahydrofuran-3-yl)methyl)amino)-8-phenyl-1,3-diazasp-
iro[4.5]decane-2,4-dione) and 300 mg of mixture of both isomers.
Reverse phase preparative HPLC conditions: mobile phase: 10 mM
ammonium bicarbonate in H.sub.2O/acetonitrile, column: X-BRIDGE-C18
(150*30), 5 .mu.m, gradient (T/B %): 0/35, 8/55, 8.1/98, 10/98,
10.1/35, 13/35, flow rate: 25 ml/min, diluent; mobile
phase+THF.
Step 9:
CIS-8-(methyl((tetrahydrofuran-3-yl)methyl)amino)-8-phenyl-1,3-dia-
zaspiro[4.5]decan-2-one (INT-1026)
[0280] LiAlH.sub.4 (1M in THF) (4.48 mL, 4.48 mmol) was added to a
solution of
CIS-8-(methyl((tetrahydrofuran-3-yl)methyl)amino)-8-phenyl-1,3-diazaspiro-
[4.5]decane-2,4-dione (isomer-1) (0.4 g, 1.12 mmol) in
THF:Et.sub.2O (2:1 v/v, 15 mL) at 0.degree. C. under argon
atmosphere. The reaction mixture was stirred at 65.degree. C. for
16 h. The mixture was cooled to 0.degree. C., quenched with sat.
aq. Na.sub.2SO.sub.4 (1000 mL) and filtered through celite pad. The
filtrate was dried over anhydrous Na.sub.2SO.sub.4 and concentrated
in vacuo. The residue was purified by column chromatography (silica
gel 230-400 mesh; 5-6% MeOH in DCM) to yield 0.3 g (78%) of
CIS-8-(methyl((tetrahydrofuran-3-yl)methyl)amino)-8-phenyl-1,3-diazaspiro-
[4.5]decan-2-one (INT-1026) as an off white solid. (TLC system: 10%
MeOH in DCM, R.sub.f: 0.2). LC-MS: m/z [M+1].sup.+=344.2.
Synthesis of INT-1031:
CIS-1-(Cyclobutyl-methyl)-8-dimethylamino-8-(3-fluorophenyl)-1,3-diazaspi-
ro[4.5]decan-2-one
##STR00041##
[0281] Step 1:
CIS-1-(Cyclobutyl-methyl)-8-dimethylamino-8-(3-fluorophenyl)-3-[(4-methox-
yphenyl)-methyl]-1,3-diazaspiro[4.5]decan-2-one
[0282] In analogy to the method described for INT-952
CIS-8-dimethylamino-8-(3-fluorophenyl)-3-[(4-methoxyphenyl)-methyl]-1,3-d-
iazaspiro[4.5]decan-2-one (INT-974) was converted into
CIS-1-(cyclobutyl-methyl)-8-dimethylamino-8-(3-fluorophenyl)-3-[(4-methox-
yphenyl)-methyl]-1,3-diazaspiro[4.5]decan-2-one.
Step 2:
CIS-1-(Cyclobutyl-methyl)-8-dimethylamino-8-(3-fluorophenyl)-1,3-d-
iazaspiro[4.5]decan-2-one
[0283] In analogy to the method described for INT-982 step 2
1-(cyclobutyl-methyl)-8-dimethylamino-8-(3-fluorophenyl)-3-[(4-methoxyphe-
nyl)-methyl]-1,3-diazaspiro[4.5]decan-2-one was converted into
1-(cyclobutyl-methyl)-8-dimethylamino-8-(3-fluorophenyl)-1,3-diazaspiro[4-
.5]decan-2-one (INT-1031).
Synthesis of INT-1037:
8-(dimethylamino)-2-oxo-1,3-diazaspiro[4.5]decane-8-carbonitrile
##STR00042##
[0284] Step 1: 9,12-dioxa-2,4-diazadispiro[4.2.4 {8}0.2
{5}]tetradecan-3-one
[0285] Lithiumaluminumhydride (2.2 equiv., 292 mmol) was suspended
in THF (400 mL) and the suspension was cooled to 0.degree. C.
8-(Dimethylamino)-8-(m-tolyl)-1,3-diazaspiro[4.5]decan-2-one (B, 75
mg, 0,261 mmol) (step 1 of INT-965) was added portionwise at
0.degree. C. The reaction mixture was stirred 1.5 h at 0.degree.
C., then overnight at RT and then 2 h at 40.degree. C. The reaction
mixture was cooled down to 0.degree. C., quenched carefully with
sat. aq. Na.sub.2SO.sub.4, EtOAc (400 mL) was added and the
resulting mixture was stirred for 2 h and then left without
stirring for 2 h at RT. The precipitate was filtered off and washed
with EtOAc and MeOH. The resulting solid residue was suspended in
methanol and stirred at RT overnight. The precipitate was filtered
off and disposed. The filtrate was concentrated under reduced
pressure, the residue was suspended thoroughly in water (50 mL) at
40.degree. C., the precipitate was filtered off and dried under
reduced pressure to yield 9,12-dioxa-2,4-diazadispiro[4.2.4 {8}0.2
{5}]tetradecan-3-one (11.4 g, 41%). Mass: m/z 213.2
(M+H).sup.+.
Step 2: 1,3-diazaspiro[4.5]decane-2,8-dione
[0286] In analogy to the method described for INT-1003 step 3
9,12-dioxa-2,4-diazadispiro[4.2.4 {8}0.2 {5}]tetradecan-3-one was
treated with conc. aq. HCl to be converted into
1,3-diazaspiro[4.5]decane-2,8-dione. Mass: m/z 169.1
(M+H).sup.+.
Step 3:
8-(dimethylamino)-2-oxo-1,3-diazaspiro[4.5]decane-8-carbonitrile
(INT-1037)
[0287] In analogy to the method described for INT-965 step 1
1,3-diazaspiro[4.5]decane-2,8-dione was treated with dimethyl amine
and potassium cyanide to be converted into
8-(dimethylamino)-2-oxo-1,3-diazaspiro[4.5]decane-8-carbonitrile
(INT-1037). Mass: m/z 223.2 (M+H).sup.+.
Synthesis of INT-1038:
CIS-8-(dimethylamino)-8-(m-tolyl)-1,3-diazaspiro[4.5]decan-2-one
##STR00043##
[0289] To the suspension of
8-(dimethylamino)-2-oxo-1,3-diazaspiro[4.5]decane-8-carbonitrile
(200 mg, 0.90 mmol) in THF (4 mL) at RT was added dropwise 1M
bromo(m-tolyl)magnesium in THF (4 equiv., 3.6 mmol, 3.6 mL) and the
reaction mixture was stirred for 1 h at RT. Additional portion of
1M bromo(m-tolyl)magnesium in THF (1 equiv., 0.8 mL) was added. The
reaction mixture was stirred at RT overnight, then quenched with
methanol/water. Solid NH.sub.4Cl and DCM were added to the
resulting mixture and the precipitate was filtered off. The organic
phase of the filtrate was separated and the aqueous phase was
extracted with DCM (3.times.). The combined organic phases were
dried over anhydr. Na.sub.2SO.sub.4 and concentrated under reduced
pressure. The residue was purified by flash chromatography on
silica gel (DCM/MeOH, 100/0 to 65/35) to yield
CIS-8-(dimethylamino)-8-(m-tolyl)-1,3-diazaspiro[4.5]decan-2-one
(INT-1038) (81 mg, 31%). Mass: m/z 288.2 (M+H)+.
Synthesis of INT-1059:
TRANS-8-(dimethylamino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one
##STR00044##
[0290] Step 1:
TRANS-8-(dimethylamino)-8-phenyl-1,3-diazaspiro[4.5]decane-2,4-dione
[0291] To a stirred solution of
4-dimethylamino-4-phenyl-cyclohexanone (250.0 g, 1.15 mol, 1.0 eq.)
in EtOH (2.5 L) and water (2.1 L) was added
(NH.sub.4).sub.2CO.sub.3 (276.2 g, 2.87 mol, 2.5 eq.) and the
reaction mixture was stirred at RT for 15 min. KCN (74.92 g, 1.15
mol, 1.0 eq.) was added. The reaction mixture was stirred at
60.degree. C. for 18 h and then filtered in hot condition to get
white solid which was washed with water (2.5 L), ethanol (1 L) and
hexane (2.5 L). The resulting solid was dried under reduced
pressure to get
CIS-8-dimethylamino-8-phenyl-1,3-diaza-spiro[4.5]decane-2,4-dione
(223 g, 0.776 mol, 65%) as a white solid. The filtrate was
collected from multiple batches (.about.450 g) which contained a
mixture of cis and trans isomers. The filtrate was concentrated
under reduced pressure and solid obtained was filtered and washed
with water (1 L) and hexane (1 L). Solid material was dried under
reduced pressure to get .about.100 g of a mixture of cis and trans
(major) isomers. Crude material was partially dissolved in hot MeOH
(600 mL) and cooled to RT, filtered through sintered funnel, washed
with MeOH (200 mL) followed by ether (150 mL) and dried to get
TRANS-8-dimethylamino-8-phenyl-1,3-diaza-spiro[4.5]decane-2,4-dione
(50 g, 0.174 mmol, .about.9-10%).
Step 2:
TRANS-8-(dimethylamino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one
(INT-1059)
[0292] In analogy to the method described for INT-976 step 2
TRANS-8-dimethylamino-8-phenyl-1,3-diaza-spiro[4.5]decane-2,4-dione
was treated with LiAlH.sub.4 to be converted into
TRANS-8-(dimethylamino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one
(INT-1059). Mass: m/z 274.2 (M+H)+.
Synthesis of INT-1068 and INT-1069: CIS- and
TRANS-8-(dimethylamino)-8-phenyl-1-(2,2,2-trifluoroethyl)-1,3-diazaspiro[-
4.5]decan-2-one
##STR00045##
[0293] Step 1:
1-amino-4-dimethylamino-4-phenyl-cyclohexanecarbonitrile
[0294] To a stirred solution of
4-dimethylamino-4-phenyl-cyclohexanone (50 g, 230.096 mmol) in MeOH
(400 mL) was added NH.sub.4Cl (24.6 g, 460.8 mmol) followed by
NH.sub.4OH (400 mL) at RT and the reaction mixture was stirred for
15 min. NaCN (22.5 g, 460.83 mmol) was added and the resulting
mixture was stirred for 16 h at RT. The reaction mixture was
extracted with DCM (3.times.750 mL). Combined organic layer was
washed with water (750 mL), brine (750 mL), dried over
Na.sub.2SO.sub.4 and concentrated under reduced pressure. The
residue was triturated with DCM/hexane to get crude
1-amino-4-dimethylamino-4-phenyl-cyclohexanecarbonitrile (50 g,
90%) as an off white solid which was used in next step without
further purification. LC-MS: m/z [M+H].sup.+=244.2 (MW calc.
244.09).
Step 2:
N-(1-cyano-4-dimethylamino-4-phenyl-cyclohexyl)-2,2,2-trifluoroace-
tamide
[0295] To a solution of
1-amino-4-dimethylamino-4-phenyl-cyclohexanecarbonitrile (5.0 g,
20.57 mmol, 1.0 eq.) in THF (100 ml) were added DIPEA (10.72 ml,
61.71 mmol, 3.0 eq), trifluoroacetic acid (1.89 ml, 24.69 mmol, 1.2
eq) and T3P (18.2 ml, 30.85 mmol, 1.5 eq) at 0.degree. C. The
reaction mixture was stirred at RT for 16 h, then diluted with
water (100 ml) and extracted with 10% MeOH in DCM (2.times.250 mL).
Combined organic layer was washed with brine (100 mL), dried over
Na.sub.2SO.sub.4 and concentrated under reduced pressure to get
crude
N-(1-cyano-4-dimethylamino-4-phenyl-cyclohexyl)-2,2,2-trifluoroacetamide
as a light yellow sticky material which was used in the next step
without further purification. LC-MS: m/z [M+1].sup.+=339.9 (MW
calc. 339.36).
Step 3:
1-aminomethyl-N',N'-dimethyl-4-phenyl-N-(2,2,2-trifluoroethyl)cycl-
ohexane-1,4-diamine
[0296] To suspension of LiAlH.sub.4 (4.03 g, 106.19 mmol, 6.0 eq.)
in dry THF (40 mL) was added
N-(1-cyano-4-dimethylamino-4-phenyl-cyclohexyl)-2,2,2-trifluoro-acetamide
(6.0 g, 17.69 mmol, 1.0 eq.) in dry THF (100 mL) dropwise at
0.degree. C. The reaction mixture was stirred at RT for 16 h, then
quenched with sat. aq. Na.sub.2SO.sub.4 at 0.degree. C., excess THF
was added and the resulting mixture was stirred at RT for 2 h. The
resulting suspension was filtered through celite and the filter
cake was washed with 10% MeOH in DCM (150 mL). Combined filtrate
was concentrated under reduced pressure to yield crude
1-aminomethyl-N',N'-dimethyl-4-phenyl-N-(2,2,2-trifluoro-ethyl)-cyclohexa-
ne-1,4-diamine (4.2 g, crude) as a light yellow sticky material
which was directly used in the next step without further
purification. LC-MS: m/z [M+1].sup.+=330.0 (MW calc. 329.40).
Step 4: CIS- and
TRANS-8-dimethylamino-8-phenyl-1-(2,2,2-trifluoro-ethyl)-1,3-diaza-spiro[-
4.5]decan-2-one (INT-1068 and INT-1069)
[0297] To a solution of
1-aminomethyl-N',N'-dimethyl-4-phenyl-N-(2,2,2-trifluoro-ethyl)-cyclohexa-
ne-1,4-diamine (4.2 g, 12.76 mmol, 1.0 eq.) in toluene (60 ml) was
added KOH (4.29 g, 76.56 mmol, 6.0 eq.) in water (120 ml) at
0.degree. C. followed by addition of COCl.sub.2 (15.6 ml, 44.66
mmol, 3.5 eq., 20% in toluene) at 0.degree. C. and stirred at RT
for 16 h. Reaction mixture was basified with sat NaHCO.sub.3
solution and extracted with DCM (2.times.200 ml). Combined organic
layer was dried over Na.sub.2SO.sub.4 and concentrated under
reduced pressure to get crude product which was purified by prep
HPLC to get
CIS-8-dimethylamino-8-phenyl-1-(2,2,2-trifluoro-ethyl)-1,3-diaza-spiro[4.-
5]decan-2-one (INT-1068) (1.5 g) (major isomer, polar spot on TLC)
and
TRANS-8-dimethylamino-8-phenyl-1-(2,2,2-trifluoro-ethyl)-1,3-diaza-spiro[-
4.5]decan-2-one (INT-1069) as minor isomer (non-polar spot on TLC)
(120 mg, 92.93% by HPLC) as off-white solids. CIS-isomer: LC-MS:
m/z [M+1].sup.+=356.2 (MW calc.=355.40). HPLC: 98.53%, Column:
Xbridge C-18 (100.times.4.6), 5p, Diluent: MeOH, Mobile phase: A)
0.05% TFA in water; B) ACN flow rate: 1 ml/min, R.sub.t=5.17 min.
.sup.1HNMR (DMSO-d.sub.6, 400 MHz), .delta. (ppm)=7.43-7.27 (m,
5H), 6.84 (s, 1H), 3.30-3.25 (m, 4H), 2.66-2.63 (d, 2H, J=12.72
Hz), 1.89 (s, 6H), 1.58-1.51 (m, 2H), 1.46-1.43 (m, 2H), 1.33-1.23
(m, 2H).
Synthesis of INT-1075:
CIS-3-(8-(dimethylamino)-1-((1-hydroxycyclobutyl)methyl)-2-oxo-8-phenyl-1-
,3-diazaspiro[4.5]decan-3-yl)-2,2-dimethylpropanoic acid
##STR00046##
[0299] A mixture of
CIS-3-[8-dimethylamino-1-(1-hydroxy-cyclobutylmethyl)-2-oxo-8-phenyl-1,3--
diaza-spiro[4.5]dec-3-yl]-2,2-dimethyl-propionitrile (INT-790) (2.8
g, 6.39 mmol, 1.0 eq.) and NaOH (1.02 g, 25.57 mmol, 4.0 eq.) in
ethylene glycol/water (3:1; 20 mL) was stirred at 110.degree. C.
for 36 h. The reaction mixture was acidified with aq. NaHSO.sub.4,
the precipitate was filtered off and purified by column
chromatography (silica gel; 8% MeOH/DCM) to yield
CIS-3-[8-dimethylamino-1-(1-hydroxy-cyclobutylmethyl)-2-oxo-8-phenyl-1,3--
diaza-spiro[4.5]dec-3-yl]-2,2-dimethyl-propionic acid (1.0 g, 2.188
mmol, 34%) as an off-white solid. LC-MS): m/z [M+1].sup.+=458.0 (MW
calc.=457.61).
[0300] For further intermediates the synthesis in analogy to
previously described methods is given in the following table. The
syntheses of the building blocks and intermediates have either been
described previously within this application or can be performed in
analogy to the herein described methods or by methods known to the
person, skilled in the art. Such a person will also know which
building blocks and intermediates need to be chosen for synthesis
of each exemplary compound.
TABLE-US-00002 Inter- in analogy to m/z mediate Chemical Name
Chemical Structure method [M + H].sup.+ INT-790
CIS-3-[8-Dimethylamino- 1-[(1-hydroxy-cyclobutyl)-
methyl]-2-oxo-8-phenyl- 1,3-diazaspiro[4.5]decan-
3-yl]-2,2-dimethyl- propionitrile ##STR00047## INT-897 Step 1 439.3
INT-791 CIS-3-[1-(Cyclobutyl- methyl)-8-(ethyl-methyl-
amino)-2-oxo-8-phenyl- 1,3-diazaspiro[4.5]decan-
3-yl]-2,2-dimethyl- propionitrile ##STR00048## INT-897 Step 1 437.3
INT-792 CIS-3-[8-Dimethylamino- 1-(2-methoxy-ethyl)-2-
oxo-8-phenyl-1,3- diazaspiro[4.5]decan-3-yl]-
2,2-dimethyl-propionitrile ##STR00049## INT-897 Step 1 413.3
INT-793 CIS-3-[8-Dimethylamino- 1-(3-methoxy-propyl)-2-
oxo-8-phenyl-1,3- diazaspiro[4.5]decan-3-yl]-
2,2-dimethyl-propionitrile ##STR00050## INT-897 Step 1 427.3
INT-794 CIS-3-(3,4- dimethoxybenzyl)-8- (dimethylamino)-8-phenyl-
1,3-diazaspiro[4.5]decan- 2-one ##STR00051## INT-975 424.3 INT-796
CIS-8-Dimethylamino-3- [(4-methoxyphenyl)- methyl]-8-(3-methoxy-
propyl)-1,3- diazaspiro[4.5]decan-2-one ##STR00052## INT-974 390.3
INT-797 CIS-8-(Ethyl-methyl- amino)-8-phenyl-1,3-
diazaspiro[4.5]decan-2-one ##STR00053## INT-976 288.2 INT-894
CIS-3-[1-(Cyclobutyl- methyl)-8-[methyl-(2-
methyl-propyl)-amino]-2- oxo-8-phenyl-1,3-
diazaspiro[4.5]decan-3-yl]- propionic acid; 2,2,2- trifluoro-acetic
acid salt ##STR00054## INT-898 456.3 INT-895
CIS-3-[8-Dimethylamino- 1-(2-methoxy-ethyl)-2- oxo-8-phenyl-1,3-
diazaspiro[4.5]decan-3-yl]- propionic acid; 2,2,2- trifluoro-acetic
acid salt ##STR00055## INT-898 404.2 INT-896
CIS-3-[8-Dimethylamino- 1-(3-methoxy-propyl)-2- oxo-8-phenyl-1,3-
diazaspiro[4.5]decan-3-yl]- propionic acid; 2,2,2- trifluoro-acetic
acid salt ##STR00056## INT-898 418.3 INT-949 CIS 8-Dimethylamino-1-
ethyl-8-phenyl-1,3- diazaspiro[4.5]decan-2-one ##STR00057## INT-984
302.2 INT-950 CIS-1-(Cyclobutyl- methyl)-8-dimethylamino-
8-phenyl-3-[phenyl- methyl]-1,3- diazaspiro[4.5]decan-2-one
##STR00058## INT-952 432.3 INT-954 4-Dimethylamino-4-(5-
methyl-thiophen-2-yl)- cyclohexan-1-one ##STR00059## INT-965 238.1
INT-955 4-Dimethylamino-4- thiophen-2-yl-cyclohexan- 1-one
##STR00060## INT-965 224.1 INT-956 1-(1-Methyl-1H-pyrazol-3-
yl)-4-oxo-cyclohexane-1- carbonitrile ##STR00061## INT-958 204.1
INT-957 4-Oxo-1-pyrazin-2-yl- cyclohexane-1-carbonitrile
##STR00062## INT-958 202.1 INT-959 4-Dimethylamino-4-(1-
methyl-1H-pyrazol-3-yl)- cyclohexan-1-one ##STR00063## INT-961
222.2 INT-960 4-Dimethylamino-4- pyrazin-2-yl-cyclohexan-1- one
##STR00064## INT-961 220.1 INT-962 4-Dimethylamino-4-(3-
methoxyphenyl)- cyclohexan-1-one ##STR00065## INT-965 248.2 INT-963
CIS-3-Benzyl-8- dimethylamino-8-phenyl- 1,3-diazaspiro[4.5]decan-
2-one ##STR00066## INT-975 364.2 INT-964 4-(Ethyl-methyl-amino)-4-
phenyl-cyclohexan-1-one ##STR00067## INT-965 232.2 INT-967
CIS-8-Dimethylamino-8- [4-(methoxymethyloxy)- phenyl]-3-[(4-
methoxyphenyl)-methyl]- 1,3-diazaspiro[4.5]decan- 2-one
##STR00068## INT-974 454.3 INT-968 CIS-8-Dimethylamino-8-
[3-(methoxymethyloxy)- phenyl]-3-[(4- methoxyphenyl)-methyl]-
1,3-diazaspiro[4.5]decan- 2-one ##STR00069## INT-974 454.3 INT-969
CIS-1-(Cyclobutyl- methyl)-8-dimethylamino- 8-(4-hydroxyphenyl)-3-
[(4-methoxyphenyl)- methyl]-1,3- diazaspiro[4.5]decan-2-one
##STR00070## INT-971 478.3 INT-970 CIS-8-Dimethylamino-8-
(4-methoxyphenyl)-3-[(4- methoxyphenyl)-methyl]-
1,3-diazaspiro[4.5]decan- 2-one ##STR00071## SC_2017 424.3 INT-972
CIS-8-Dimethylamino-8- (3-methoxyphenyl)-3-[(4-
methoxyphenyl)-methyl]- 1,3-diazaspiro[4.5]decan- 2-one
##STR00072## SC_2017 424.3 INT-973 CIS-8-Dimethylamino-8-
(4-fluorophenyl)-3-[(4- methoxyphenyl)-methyl]-
1,3-diazaspiro[4.5]decan- 2-one ##STR00073## INT-974 412.2 INT-979
CIS-8-Dimethylamino-1- (3-methoxy-propyl)-8- phenyl-1,3-
diazaspiro[4.5]decan-2-one ##STR00074## INT-984 346.2 INT-980
CIS-8-Dimethylamino-1- (2-methoxy-ethyl)-8- phenyl-1,3-
diazaspiro[4.5]decan-2-one ##STR00075## INT-984 332.2 INT-981
CIS-8-Dimethylamino-8- phenyl-1-propyl-1,3-
diazaspiro[4.5]decan-2-one ##STR00076## INT-984 316.2 INT-983
ClS-1-(Cyclopropyl- methyl)-8-dimethylamino- 8-phenyl-1,3-
diazaspiro[4.5]decan-2-one ##STR00077## INT-984 328.2 INT-985
CIS-1-(Cyclobutyl- methyl)-8-(methyl-propyl- amino)-8-phenyl-1,3-
diazaspiro[4.5]decan-2-one ##STR00078## INT-986 370.3 INT-993
4-benzyl-4- (dimethylamino)cyclo- hexanone ##STR00079## INT-965
232.3 INT-994 CIS-8-benzyl-8- (dimethylamino)-1,3-
diazaspiro[4.5]decan-2-one ##STR00080## INT-976 288.2 INT-995
TRANS-8-benzyl-8- (dimethylamino)-1,3- diazaspiro[4.5]decan-2-one
##STR00081## INT-976 288.2 INT-997 CIS-8-(dimethylamino)-8-
(thiophen-2-yl)-1,3- diazaspiro[4.5]decan-2-one ##STR00082##
INT-976 280.1 INT-998 TRANS-8- (dimethylamino)-8-
(thiophen-2-yl)-1,3- diazaspiro[4.5]decan-2-one ##STR00083##
INT-976 280.1 INT-999 4-(dimethylamino)-4-(1- methyl-1H-
benzo[d]imidazol-2- yl)cyclohexanone ##STR00084## INT-965 272.2
INT-1000 CIS-8-(dimethylamino)-8- (1-methyl-1H-
benzo[d]imidazol-2-yl)- 1,3-diazaspiro[4.5]decan- 2-one
##STR00085## INT-976 328.2 INT-1001 TRANS-8- (dimethylamino)-8-(1-
methyl-1H- benzo[d]imidazol-2-yl)- 1,3-diazaspiro[4.5]decan- 2-one
##STR00086## INT-976 328.2 INT-1009 TRANS-8-ethylamino-8-
phenyl-1,3-diaza- spiro[4.5]decan-2-one ##STR00087## INT-1008 274.2
INT-1013 CIS-3-(1- (cyclobutylmethyl)-2-oxo-
8-phenyl-8-(propylamino)- 1,3-diazaspiro[4.5]decan- 3-yl)-2,2-
dimethylpropanenitrile ##STR00088## SC_5068 437.3 INT-1024
CIS-8-(dimethylamino)-8- (3-fluorophenyl)-1,3-
diazaspiro[4.5]decan-2-one ##STR00089## INT-977 (step 2) 292.2
INT-1025 CIS-8-(dimethylamino)-8- (4-fluorophenyl)-1,3-
diazaspiro[4.5]decan-2-one ##STR00090## INT-974, INT-977 (step 2)
292.2 INT-1039 CIS-8-(dimethylamino)-8- (3-
(trifluoromethoxy)phenyl)- 1,3-diazaspiro[4.5]decan- 2-one
##STR00091## INT-1038 358.2 INT-1040 (CIS)-8-(dimethylamino)- 8-(3-
(trifluoromethyl)phenyl)- 1,3-diazaspiro[4.5]decan- 2-one
##STR00092## INT-1038 342.2 INT-1041 (CIS)-8-(dimethylamino)-
8-(3-methoxyphenyl)-1,3- diazaspiro[4.5]decan-2-one ##STR00093##
INT-1038 304.2 INT-1042 (CIS)-8-(5-chlorothiophen-
2-yl)-8-(dimethylamino)- 1,3-diazaspiro[4.5]decan- 2-one
##STR00094## INT-1038 314.1 INT-1043 (CIS)-8-(dimethylamino)-
8-(3-fluoro-5- methylphenyl)-1,3- diazaspiro[4.5]decan-2-one
##STR00095## INT-1038 306.2 INT-1044 (CIS)-8-(3-chlorophenyl)-
8-(dimethylamino)-1,3- diazaspiro[4.5]decan-2-one ##STR00096##
INT-1038 308.2 INT-1047 (CIS)-8-(methyl(oxetan-3-
ylmethyl)amino)-8-phenyl- 1,3-diazaspiro[4.5]decan- 2-one
##STR00097## INT-1026 330.5 INT-1061 TRANS-1-(cyclopropyl-
methyl)-8-dimethylamino- 8-phenyl-1,3- diazaspiro[4.5]decan-2-one
##STR00098## INT-984 328.2 INT-1063 CIS-1- (cyclopropylmethyl)-8-
(dimethylamino)-8-(3- fluorophenyl)-1,3- diazaspiro[4.5]decan-2-one
##STR00099## INT-1031 346.2 INT-1066 TRANS-1- (cyclobutylmethyl)-8-
(dimethylamino)-8-phenyl- 1,3-diazaspiro[4.5]decan- 2-one
##STR00100## INT-987 342.3 INT-1070 CIS-8-(dimethylamino)-8-
phenyl-1-(3,3,3- trifluoropropyl)-1,3- diazaspiro[4.5]decan-2-one
##STR00101## INT-1068 360.2 INT-1074 CIS-8-(dimethylamino)-8-
(3-fluorophenyl)-1-((1- hydroxycyclobutyl)methyl)-
1,3-diazaspiro[4.5]decan- 2-one ##STR00102## INT-1031 376.2
Synthesis of Exemplary Compounds
Synthesis of SC_5003:
CIS-3-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspir-
o[4.5]decan-3-yl]-N-(2-methoxy-pyridin-4-yl)-propionamide
##STR00103##
[0302] Into a dry tube were added successively 1 mL of a solution
of
CIS-3-[1-(cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspir-
o[4.5]decan-3-yl]-propionic acid trifluoroacetate (INT-898) (0.1 M
in DCM), 2 mL of a solution of 2-methoxypyridin-4-amine (0.2 M in
DCM), 0.07 mL of triethylamine and 0.118 mL T3P (1.7 M, 50% in
ethyl acetate). The reaction mixture was stirred at RT overnight,
quenched with 3 mL 1M aq. Na.sub.2CO.sub.3 and stirred at RT for 1
h. The organic layer was separated and the aqueous layer was
extracted with DCM (2.times.). The combined organic layers were
concentrated under reduced pressure and the product was purified by
HPLC to obtain
CIS-3-[I-(cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspir-
o[4.5]decan-3-yl]-N-(2-methoxy-pyridin-4-yl)-propionamide
(SC_5003). [M+H].sup.+520.3
Synthesis of SC_5022:
CIS-N-(2-cyano-pyrimidin-5-yl)-3-[8-dimethylamino-1-[(1-hydroxy-cyclobuty-
l)-methyl]-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-propionamide
##STR00104##
[0304]
CIS-3-[8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-2-oxo-8-ph-
enyl-1,3-diazaspiro[4.5]decan-3-yl]-propionamide (SC_5002) (0.270
g, 0.631 mmol) was dissolved in 1,4 dioxane (30 mL) at RT and
purged with nitrogen. To the reaction mixture were added
5-bromopyrimidine-2-carbonitrile (0.173 g, 0.946 mmol),
Cs.sub.2CO.sub.3 (0.410 g, 1.262 mmol), Xanthphos (0.055 g, 0.095
mmol), Pd.sub.2(dba).sub.3 (0.029 g, 0.032 mmol) and the resulting
suspension was again purged with nitrogen for 15 minutes. The
reaction mixture was stirred at 90.degree. C. for 18 h, then cooled
to RT and diluted with EtOAc (60 mL). The insoluble solid was
filtered off and the clear filtrate was concentrated under reduced
pressure. The crude product was purified preparative TLC using 3%
MeOH in DCM as a mobile phase to afford 52 mg (15%) of
CIS-N-(2-cyano-pyrimidin-5-yl)-3-[8-dimethylamino-1-[(1-hydroxy-cyclobuty-
l)-methyl]-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-propionamide
(SC_5022) as an off-white solid (TLC system: 10% MeOH in DCM; Rf:
0.56). [M+H].sup.+ 532.3
Synthesis of SC_5031:
CIS-3-[8-dimethylamino-1-(2-methoxy-ethyl)-2-oxo-8-phenyl-1,3-diazaspiro[-
4.5]decan-3-yl]-N-(2-hydroxy-ethyl)-propionamide
##STR00105##
[0306] 50% Propylphosphonic anhydride (T3P) solution in ethyl
acetate (0.766 mL, 1.204 mmol) was added to a solution of crude
CIS-3-[8-dimethylamino-1-(3-methoxy-propyl)-2-oxo-8-phenyl-1,3-diazaspiro-
[4.5]decan-3-yl]-propionic acid trifluoroacetate (INT-896) (100 mg,
0.193 mmol), 2-aminoethanol (0.035 mL, 0.580 mmol) and
diisopropylethylamine (0.167 mL, 0.966 mmol) in DCM (4 mL) at
0.degree. C. The reaction mixture was warmed to RT and stirred for
4 h and then quenched with water. The organic product was extracted
with DCM (3.times.20 mL). The combined organic layer was washed
with sat. aq. NaHCO.sub.3 (10 mL), brine (10 mL), dried over
anhydr. Na.sub.2SO.sub.4 and concentrated under reduced pressure.
The residue was purified by preparative HPLC to give 31 mg of
CIS-3-[8-dimethylamino-1-(2-methoxy-ethyl)-2-oxo-8-phenyl-1,3-diazaspiro[-
4.5]decan-3-yl]-N-(2-hydroxy-ethyl)propionamide (SC_5031) as an
off-white solid. [M+H].sup.+ 447.3
Synthesis of SC_5034:
CIS-3-[8-dimethylamino-1-(3-methoxy-propyl)-2-oxo-8-phenyl-1,3-diazaspiro-
[4.5]decan-3-yl]-2,2-dimethyl-propionamide
##STR00106##
[0308] 30% aq. H.sub.2O.sub.2 (0.2 mL, 0.74 mmol) was added to a
suspension of
CIS-3-[8-dimethylamino-1-(3-methoxy-propyl)-2-oxo-8-phenyl-1,3-diazaspiro-
[4.5]decan-3-yl]-2,2-dimethylpropionitrile (INT-793) (80 mg, 0.187
mmol) and K.sub.2CO.sub.3 (52 mg, 0.37 mmol) in DMSO at
10-15.degree. C. The resulting reaction mixture was warmed to RT
and stirred for 18 h. The reaction mixture was quenched with water
and the organic product was extracted with EtOAc (3.times.10 mL).
The combined organic layer was washed with brine, dried over
anhydrous Na.sub.2SO.sub.4 and concentrated under reduced pressure.
The resulting crude product was purified by preparative TLC (2%
MeOH in DCM) to yield 30 mg of
CIS-3-[8-dimethylamino-1-(3-methoxy-propyl)-2-oxo-8-phenyl-1,3-diazaspiro-
[4.5]decan-3-yl]-2,2-dimethyl-propionamide (SC_5034) (25%) as an
off-white solid. (TLC system: 10% MeOH in DCM R.sub.f: 0.40).
[M+H].sup.+445.3
Synthesis of SC-5055:
CIS-3-[8-dimethylamino-1-[(l-hydroxy-cyclobutyl)-methyl]-2-oxo-8-phenyl-1-
,3-diazaspiro[4.5]decan-3-yl]-N-(oxetan-3-yl)-propionamide
##STR00107##
[0310] 50% Propylphosphonic anhydride (T3P) solution in DMF (1.1
mL, 1.748 mmol) was added to a mixture of crude
CIS-3-[8-dimethylamino-l-[(1-hydroxy-cyclobutyl)-methyl]-2-oxo-8-phenyl-1-
,3-diazaspiro[4.5]decan-3-yl]-propionic acid (INT-899) (300 mg,
0.699 mmol, crude, contaminated with 4-methylbenzene-sulfonic
acid), oxetan-3-amine hydrochloride (91 mg, 0.839 mmol) and
diisopropylethylamine (0.51 mL, 2.797 mmol) in DMF (6 mL) at
0.degree. C. The reaction mixture was warmed to RT and stirred for
6 h, then quenched with water and the organic product was extracted
with EtOAc (3.times.20 mL). The combined organic layer was washed
with sat. aq. NaHCO.sub.3 (10 mL), brine (10 mL), dried over
anhydr. Na.sub.2SO.sub.4 and concentrated under reduced pressure.
The crude product was purified by preparative TLC by using 3%
methanol in DCM as a mobile phase to yield 140 mg (41%) of
CIS-3-[8-dimethylamino-l-[(1-hydroxy-cyclobutyl)-methyl]-2-oxo-8-phenyl-1-
,3-diazaspiro[4.5]decan-3-yl]-N-(oxetan-3-yl)-propionamide
(SC_5055) as an off-white solid. (TLC system: 10% MeOH in DCM
R.sub.f: 0.55). [M+H].sup.+ 485.3
Synthesis of SC_5056:
CIS-N-(carbamoyl-methyl)-3-[1-(cyclobutyl-methyl)-8-dimethyl-amino-2-oxo--
8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-2,2-dimethyl-propionamide
##STR00108##
[0312] 50% propylphosphonic anhydride (T3P) solution in DMF (3.99
mL, 6.27 mmol) was added to a solution of
CIS-3-[1-(cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspir-
o[4.5]decan-3-yl]-2,2-dimethyl-propionic acid (INT-897) (1.2 g,
2.51 mmol), 2-aminoacetamide hydrochloride (0.41 g, 3.76 mmol) and
diisopropylethylamine (2.63 mL, 15.06 mmol) in DMF (15 mL) at
0.degree. C. The reaction mixture was warmed to RT and stirred for
16 h. The reaction mixture was quenched with water, the organic
product was extracted with DCM (3.times.15 mL). The combined
organic extracts were washed with brine, dried over anhydr.
Na.sub.2SO.sub.4 and concentrated under reduced pressure. The
resulting crude product was purified by reverse phase preparative
HPLC to give 105 mg of
CIS-N-(carbamoyl-methyl)-3-[1-(cyclobutyl-methyl)-8-dimethyl-amino-2-oxo--
8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-2,2-dimethyl-propionamide
(SC_5056) as an off-white solid. (TLC system: 10% MeOH in DCM
R.sub.f: 0.4). [M+H].sup.+ 442.3
Synthesis of SC_5059:
CIS-3-[1-[(1-hydroxy-cyclobutyl)-methyl]-8-methylamino-2-oxo-8-phenyl-1,3-
-diazaspiro[4.5]decan-3-yl]-N-(oxetan-3-yl)-propionamide
##STR00109##
[0314] N-Iodosuccinimide (104.6 mg, 0.465 mmol) was added to a
solution of
CIS-3-[8-dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-2-oxo-8-phenyl-1-
,3-diazaspiro[4.5]decan-3-yl]-N-(oxetan-3-yl)-propionamide
(SC_5055) (150 mg, 0.309 mmol) in a mixture of acetonitrile and THF
(1:1 v/v, 8 mL) at 0.degree. C. and the resulting mixture was
stirred for 16 h at RT. The reaction mixture was basified with 2N
aq. NaOH to pH.about.10 and the organic product was extracted with
EtOAc (3.times.30 mL). The combined organic extracts were dried
over anhydr. Na.sub.2SO.sub.4 and concentrated in vacuo. The
resulting crude product was purified by preparative reverse phase
HPLC to give 70 mg of the desired product as a formic acid salt.
The isolated product was diluted with water (8 mL) and basified
with solid NaHCO.sub.3. The resulting mixture was extracted with
ethyl acetate (2.times.30 mL), the combined organic layer was dried
over anhydr. Na.sub.2SO.sub.4 and concentrated in vacuo to yield 60
mg (41%) of
CIS-3-[1-[(1-hydroxy-cyclobutyl)-methyl]-8-methylamino-2-oxo-8-phenyl--
1,3-diazaspiro[4.5]decan-3-yl]-N-(oxetan-3-yl)-propionamide
(SC_5059) as an off-white solid (TLC system: 5% MeOH in DCM;
R.sub.f: 0.44.). [M+H].sup.+ 471.3
Synthesis of SC_5063:
CIS-2,2-dimethyl-3-(8-(methylamino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]dec-
an-3-yl)propanenitrile
##STR00110##
[0315] Step 1:
CIS-3-(8-(dimethylamino)-1-(methoxymethyl)-2-oxo-8-phenyl-1,3-diazaspiro[-
4.5]decan-3-yl)-2,2-dimethylpropanenitrile
[0316] To a solution of
CIS-3-(8-dimethylamino-2-oxo-8-phenyl-1,3-diaza-spiro[4.5]dec-3-yl)-2,2-d-
imethyl-propionitrile (SC_5062) (1.8 g, 5.08 mmol, 1.0 eq.) in THF
(20 ml) was added NaH (95%, 366 mg, 15.25 mmol, 3.0 eq.) at
0.degree. C. and the reaction mixture was stirred for 20 min at RT.
A solution of methoxymethyl chloride (0.57 ml, 7.62 mmol, 1.5 eq.)
in THF (5 ml) was added at 0.degree. C. and the resulting mixture
was stirred at RT for 16 h. The reaction mixture was diluted with
water (20 ml) and extracted with EtOAc (2.times.50 ml). The
combined organic layers were washed with water (50 ml) and brine
(50 ml), dried over anhydr. Na.sub.2SO.sub.4 and concentrated under
reduced pressure. The resulting crude product was purified by
column chromatography (neutral alumina; 0.2% MeOH/DCM) to yield
CIS-3-(8-(dimethylamino)-1-(methoxymethyl)-2-oxo-8-phenyl-1,3-diaza-
spiro[4.5]decan-3-yl)-2,2-dimethylpropanenitrile (700 mg, 1.75
mmol, 34%) as an off-white sticky solid. LC-MS: m/z
[M+H].sup.+=399.3 (MW calc.=398.54).
Step 2:
CIS-3-(1-(methoxymethyl)-8-(methylamino)-2-oxo-8-phenyl-1,3-diazas-
piro[4.5]decan-3-yl)-2,2-dimethylpropanenitrile
[0317] To a solution of
CIS-3-(8-(dimethylamino)-1-(methoxymethyl)-2-oxo-8-phenyl-1,3-diazaspiro[-
4.5]decan-3-yl)-2,2-dimethylpropanenitrile (700 mg, 1.75 mmol, 1.0
eq.) in acetonitrile (20 ml) and THF (10 ml) was added
N-iodosuccinimide (590 mg, 2.63 mmol, 1.5 eq.) at 0.degree. C. and
the mixture was stirred at RT for 3 h. The reaction mixture was
diluted with water (20 ml) and 1N aq. NaOH (5 ml) and extracted
with DCM (2.times.30 ml). The combined organic layers were washed
with brine (40 ml), dried over anhydr. Na.sub.2SO.sub.4 and
concentrated under reduced pressure to give
CIS-3-(1-(methoxymethyl)-8-(methylamino)-2-oxo-8-phenyl-1,3-diazaspiro[4.-
5]decan-3-yl)-2,2-dimethylpropanenitrile (350 mg, 0.911 mmol, 52%)
which was used directly for next step without further purification.
LC-MS: m/z [M+H].sup.+=385.2 (MW calc.=384.52).
Step 3:
CIS-2,2-dimethyl-3-(8-(methylamino)-2-oxo-8-phenyl-1,3-diazaspiro[-
4.5]decan-3-yl)propanenitrile (SC_5063)
[0318] To a solution of
CIS-3-(1-(methoxymethyl)-8-(methylamino)-2-oxo-8-phenyl-1,3-diazaspiro[4.-
5]decan-3-yl)-2,2-dimethylpropanenitrile (400 mg, 1.04 mmol, 1.0
eq.) in MeOH (10 ml) was added 2M aq. HCl (30 ml) at 0.degree. C.
and the mixture was stirred at RT for 16 h. The reaction mixture
was basified with 2M aq. NaOH and extracted with DCM (2.times.25
ml). The combined organic layers were washed with brine (30 ml),
dried over anhydr. Na.sub.2SO.sub.4 and concentrated under reduced
pressure to give
CIS-2,2-dimethyl-3-(8-(methylamino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]dec-
an-3-yl)propanenitrile (SC_5063) (300 mg, 0.882 mmol, 84%) which
was 95.72% pure according to HPLC. LC-MS: m/z [M+H]+=341.27 (MW
calc.=340.46). .sup.1HNMR (DMSO-d6, 400 MHz), .delta.
(ppm)=7.42-7.19 (m, 5H), 6.78 (bs, 1H), 3.36 (s, 2H), 3.18 (s, 2H),
1.96-1.85 (m, 7H), 1.66 (bs, 2H), 1.46-1.43 (m, 2H), 1.25 (s,
6H).
Synthesis of SC_5074:
CIS-3-(8-(ethyl(methyl)amino)-1-((1-hydroxycyclobutyl)methyl)-2-oxo-8-phe-
nyl-1,3-diazaspiro[4.5]decan-3-yl)-2,2-dimethylpropanamide
##STR00111##
[0319] Step 1:
CIS-3-(8-(ethyl(methyl)amino)-1-((1-hydroxycyclobutyl)methyl)-2-oxo-8-phe-
nyl-1,3-diazaspiro[4.5]decan-3-yl)-2,2-dimethylpropanenitrile
[0320] To a solution of
CIS-3-(8-(ethyl(methyl)amino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-y-
l)-2,2-dimethylpropanenitrile (SC_5061) (250 mg, 0.679 mmol, 1.0
eq.) in DMSO (10 ml) was added NaOH (108 mg, 2.716 mmol, 4.0 eq.)
at RT and the reaction mixture was stirred at 60.degree. C. for 30
min. A solution of 1-oxa-spiro[2.3]hexane (142 mg, 1.69 mmol, 2.5
eq.) in DMSO (1 ml) was added at RT. The reaction mixture was
stirred at 55.degree. C. for 16 h, then diluted with water (100 ml)
and extracted with ethyl acetate (60 ml). The organic layer was
washed with water (50 ml) and brine (50 ml), dried over anhydr.
Na.sub.2SO.sub.4 and concentrated under reduced pressure. The
resulting crude product was purified by column chromatography
(neutral alumina; 30% ethyl acetate/hexane) to yield
CIS-3-(8-(ethyl(methyl)amino)-1-((1-hydroxycyclobutyl)methyl)-2-oxo-8-phe-
nyl-1,3-diazaspiro[4.5]decan-3-yl)-2,2-dimethylpropanenitrile (120
mg, 0.265 mmol, 39%) as an off-white solid. LC-MS: m/z
[M+1].sup.+=453.1 (MW calc. 452.63).
Step 2:
CIS-3-(8-(ethyl(methyl)amino)-1-((1-hydroxycyclobutyl)methyl)-2-ox-
o-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-2,2-dimethylpropanamide
(SC_5074)
[0321] In analogy to the method described for SC_5034
CIS-3-(8-(ethyl(methyl)amino)-1-((1-hydroxycyclobutyl)methyl)-2-oxo-8-phe-
nyl-1,3-diazaspiro[4.5]decan-3-yl)-2,2-dimethylpropanenitrile was
treated with 30% aq. H.sub.2O.sub.2 in the presence of DMSO and
potassium carbonate to be converted into
CIS-3-(8-(ethyl(methyl)amino)-1-((1-hydroxycyclobutyl)methyl)-2-oxo-8-phe-
nyl-1,3-diazaspiro[4.5]decan-3-yl)-2,2-dimethylpropanamide
(SC_5074). Yield: 44% (55 mg, 0.117 mmol). LC-MS: m/z
[M+H].sup.+=471.1 (MW calc.=470.65). .sup.1HNMR (DMSO-d6, 400 MHz),
.delta. (ppm)=7.34-722 (m, 5H), 7.16 (s, 1H), 6.95 (s, 1H), 6.11
(s, 1H), 3.25 (s, 2H), 3.16 (s, 2H), 3.09 (s, 2H), 2.68-2.65 (m,
2H), 2.20-1.99 (m, 6H), 1.95-1.87 (m, 5H), 1.63-1.61 (m, 1H),
1.43-1.23 (m, 6H), 1.02 (s, 6H), 0.99 (t, 3H, J=6.94 Hz).
Synthesis of SC_5075:
CIS-3-(1-(cyclopropylmethyl)-8-(dimethylamino)-2-oxo-8-phenyl-1,3-diazasp-
iro[4.5]decan-3-yl)-2,2-dimethylpropanenitrile
##STR00112##
[0323]
CIS-1-(cyclopropylmethyl)-8-(dimethylamino)-8-phenyl-1,3-diazaspiro-
[4.5]decan-2-one (INT-984) (50 mg, 0.15 mmol) was added to a
suspension of NaH (60% in mineral oil, 18 mg, 0.45 mmol) in DMF (5
mL) at 0.degree. C. and the reaction mixture was stirred at RT for
5 min. 2-Cyano-2-methylpropyl 4-methylbenzenesulfonate (113 mg,
0.45 mmol) was added at 0.degree. C. and stirring was continued
120.degree. C. for 16 h. The reaction mixture was quenched with
cold water and the organic product was extracted with DCM
(3.times.20 mL). The combined organic extracts were dried over
anhydr. Na.sub.2SO.sub.4 and concentrated under reduced pressure.
The above described reaction was repeated with 300 mg of
CIS-1-(cyclopropylmethyl)-8-(dimethylamino)-8-phenyl-1,3-diazaspiro[4.5]d-
ecan-2-one (INT-984). Both reaction batches were combined and
purified by column chromatography (silica gel 100-200 mesh, 0-10%
MeOH in DCM) to yield the product which was further purified by
reverse phase preparative HPLC to afford 41 mg (16%) of
CIS-3-(1-(cyclopropylmethyl)-8-(dimethylamino)-2-oxo-8-phenyl-1,3-diazasp-
iro[4.5]decan-3-yl)-2,2-dimethylpropanenitrile (SC_5075) as an
off-white solid. (TLC system: 10% MeOH in DCM; Rf: 0.40). .sup.1H
NMR (DMSO-d6): .delta. 7.37-7.23 (m, 5H), 3.38 (s, 2H), 3.22 (s;
2H), 2.94 (d, 2H), 2.71-2.68 (m, 2H), 2.18 (t, 2H), 1.97 (s, 6H),
1.42-1.30 (m, 4H), 1.26 (s, 6H), 0.93-0.92 (m, 1H), 0.48-0.44 (m,
2H), 0.28-0.24 (m, 2H). [M+H].sup.+ 471.3
Synthesis of SC_5079:
CIS-8-(dimethylamino)-3-(3-(1,1-dioxidothiomorpholino)-2,2-dimethyl-3-oxo-
propyl)-1-((1-hydroxycyclobutyl)methyl)-8-phenyl-1,3-diazaspiro[4.5]decan--
2-one
##STR00113##
[0324] Step 1:
CIS-3-(2,2-dimethyl-3-oxo-3-thiomorpholinopropyl)-8-(dimethylamino)-1-((1-
-hydroxycyclobutyl)methyl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one
[0325] To a solution of
CIS-3-[8-dimethylamino-1-(1-hydroxy-cyclobutylmethyl)-2-oxo-8-phenyl-1,3--
diaza-spiro[4.5]dec-3-yl]-2,2-dimethyl-propionic acid (INT-1075)
(250 mg, 0.55 mmol, 1.0 eq) in DCM (20 mL) were added DIPEA (0.29
mL, 1.65 mmol, 3.0 eq.), HATU (209 mg, 0.55 mmol, 1.0 eq.) and
thiomorpholine (83 .mu.L, 0.82 mmol, 1.5 eq.) at 0.degree. C. The
reaction mixture was stirred at RT for 16 h, diluted with DCM (100
mL), washed with water (50 mL), sat. aq. NaHCO.sub.3 (50 mL) and
brine (50 mL). Organic layer was dried over sodium sulfate and
concentrated under reduced pressure to get crude product which was
purified by column chromatography (silica gel; 3% MeOH in DCM) to
yield
CIS-8-dimethylamino-3-(2,2-dimethyl-3-oxo-3-thiomorpholin-4-yl-propyl)-1--
(1-hydroxy-cyclobutylmethyl)-8-phenyl-1,3-diaza-spiro[4.5]decan-2-one
(220 mg, 0.40 mmol, 73%) as an off-white solid. LC-MS: m/z
[M+1].sup.+=543.3 (MW calc.=5'12.78).
Step 2:
CIS-8-(dimethylamino)-3-(3-(1,1-dioxidothiomorpholino)-2,2-dimethy-
l-3-oxopropyl)-1-((1-hydroxycyclobutyl)methyl)-8-phenyl-1,3-diazaspiro[4.5-
]decan-2-one (SC_5079)
[0326] To a solution of
CIS-8-dimethylamino-3-(2,2-dimethyl-3-oxo-3-thiomorpholin-4-yl-propyl)-1--
(1-hydroxy-cyclobutylmethyl)-8-phenyl-1,3-diaza-spiro[4.5]decan-2-one
(270 mg, 0.5 mmol, 1.0 eq) in acetone/THF/H.sub.2O (40 mL, 6/1/1
v/v/v) was added oxone (615 mg, 1.0 mmol, 2.0 eq.) at 0.degree. C.
The reaction mixture was stirred at RT for 16 h, quenched with sat.
aq. Na.sub.2SO.sub.3, diluted with EtOAc (150 mL) and washed with
sat. aq. NaHCO.sub.3 (75 mL). Organic layer was dried over sodium
sulfate and concentrated under reduced pressure to get crude
product which was purified by column chromatography (silica gel; 4%
MeOH in DCM) to yield
CIS-8-dimethylamino-3-[3-(1,1-dioxo-116-thiomorpholin-4-yl)-2,2-dimethyl--
3-oxo-propyl]-1-(1-hydroxy-cyclobutylmethyl)-8-phenyl-1,3-diaza-spiro[4.5]-
decan-2-one (SC_5079) (100 mg, 0.17 mmol, 34%) as a white solid.
.sup.1HNMR (DMSO-d.sub.6, 400 MHz), .delta. (ppm)=7.37-7.25 (m,
5H), 5.91 (s, 1H), 3.92 (bs, 4H), 3.28 (bs, 4H), 3.13 (bs, 4H),
3.07 (s, 2H), 2.64 (d, 2H, J=13.44 Hz), 2.07-2.00 (m, 4H), 1.96 (s,
6H), 1.87-1.85 (m, 2H), 1.61-1.64 (m, 1H), 1.40-1.30 (m, 5H), 1.19
(s, 6H). LC-MS: m/z [M+1].sup.+=575.1 (MW calc.=574.78).
Synthesis of SC_5083:
CIS-3-(1-(cyclopropylmethyl)-8-(dimethylamino)-8-(3-fluorophenyl)-2-oxo-1-
,3-diazaspiro[4.5]decan-3-yl)-N,N-dimethylpropanamide
##STR00114##
[0327] Step 1: sodium
CIS-3-(1-(cyclopropylmethyl)-8-(dimethylamino)-8-(3-fluorophenyl)-2-oxo-1-
,3-diazaspiro[4.5]decan-3-yl)propanoate
[0328] To a solution of
CIS-1-(cyclopropylmethyl)-8-(dimethylamino)-8-(3-fluorophenyl)-1,3-diazas-
piro[4.5]decan-2-one (INT-1063) (100 mg, 0.29 mmol) in dry THF (2.4
mL) cooled to 0.degree. C. was added potassium tert-butoxide (1.5
equiv., 0.43 mmol, 49 mg). The reaction mixture was stirred for 15
min at 0.degree. C. and methyl 3-bromopropionate (1.2 equiv., 0.35
mmol, 38 .mu.L) was added dropwise. The reaction mixture was
stirred at RT for 16 h and new portions of methyl 3-bromopropionate
(1.2 equiv., 0.35 mmol, 38 .mu.L) and potassium tert-butoxide (1.5
equiv., 0.43 mmol, 49 mg) were added. The reaction mixture was
stirred for 3 h at RT, quenched with sat. aq. NaHCO.sub.3 and then
extracted with DCM (2.times.). To the combined organic phase 2 mL
of 2M aq. NaOH were added, the resulting mixture was vigorously
stirred overnight at RT and then concentrated under reduced
pressure to yield crude sodium
CIS-3-(l-(cyclopropylmethyl)-8-(dimethylamino)-8-(3-fluorophenyl)-2-oxo-1-
,3-diazaspiro[4.5]decan-3-yl)propanoate (60 mg, 50%) which was used
in the next step without further purification. LC-MS: m/z
[M+1].sup.+=418.3 (MW calc. 417.3)
Step 2:
CIS-3-(1-(cyclopropylmethyl)-8-(dimethylamino)-8-(3-fluorophenyl)--
2-oxo-1,3-diazaspiro[4.5]decan-3-yl)-N,N-dimethylpropanamide
(SC_5083)
[0329] To a solution of sodium
CIS-3-[1-(cyclopropylmethyl)-8-(dimethylamino)-8-(3-fluorophenyl)-2-oxo-1-
,3-diazaspiro[4.5]decan-3-yl]propanoate (60 mg, 0.144 mmol, 60 mg)
and N-methylmethanamine (8 equiv., 1.15 mmol, 2 M in THF, 0.57 mL)
in DCM (1 mL) was added propylphosphonic anhydride solution>50
wt. % in EtOAc (2 equiv., 0.29 mmol, 0.17 mL). The reaction mixture
was stirred at RT overnight, then quenched with sat. aq.
NaHCO.sub.3 (2 mL) and diluted with EtOAc. The organic phase was
separated and the aqueous phase extracted with EtOAc. The combined
organic layers were dried over anhydr. Na.sub.2SO.sub.4 and
concentrated under reduced pressure. The resulting crude product
was purified by flash chromatography (eluent gradient DCM/MeOH) to
yield
CIS-3-(1-(cyclopropylmethyl)-8-(dimethylamino)-8-(3-fluorophenyl)-2-oxo-1-
,3-diazaspiro[4.5]decan-3-yl)-N,N-dimethylpropanamide (SC_5083) (25
mg, 39%). LC-MS: m/z [M+H].sup.+=445.3 (MW calc.=444.29). .sup.1H
NMR (600 MHz, DMSO) .delta. 7.40 (td, 1H), 7.21-7.05 (m, 3H), 3.27
(t, 2H), 3.18 (s, 2H), 2.95 (s, 3H), 2.91 (d, 2H), 2.79 (s, 3H),
2.67-2.55 (m, 2H), 2.47 (t, 2H), 2.13 (ddd, 2H), 1.99 (s, 6H),
1.43-1.21 (m, 4H), 0.92 (ddt, 1H), 0.49-0.41 (m, 2H), 0.30-0.21 (m,
2H).
[0330] For further exemplary compounds the last synthesis step in
analogy to previously described methods is given in the following
table. The syntheses of the building blocks and intermediates have
either been described previously within this application or can be
performed in analogy to the herein described methods or by methods
known to the person, skilled in the art. Such a person will also
know which building blocks and intermediates need to be chosen for
synthesis of each exemplary compound.
TABLE-US-00003 in analogy m/z Example Chemical Name Reactant I
Reactant II to method [M + H].sup.+ SC_5001
CIS-3-[8-Dimethylamino-1-[(1-hydroxy- INT 899 pyridazin-3- SC_5055
507.3 cyclobutyl)-methyl]-2-oxo-8-phenyl-1,3- amine
diazaspiro[4.5]decan-3-yl]-N-pyridazin-3- yl-propionamide SC_5002
CIS-3-[8-Dimethylamino-1-[(1-hydroxy- INT 899 NH.sub.4Cl SC_5055
429.3 cyclobutyl)-methyl]-2-oxo-8-phenyl-1,3-
diazaspiro[4.5]decan-3-yl]-propionamide SC_5004
CIS-3-[1-(Cyclobutyl-methyl)-8- INT 998 6- SC_5003 520.3
dimethylamino-2-oxo-8-phenyl-1,3- methoxypyridin-
diazaspiro[4.5]decan-3-yl]-N-(6-methoxy- 3-amine
pyridin-3-yl)-propionamide SC_5005 CIS-3-[1-(Cyclobutyl-methyl)-8-
INT 998 3- SC_5003 520.3 dimethylamino-2-oxo-8-phenyl-1,3-
methoxypyridin- diazaspiro[4.5]decan-3-yl]-N-(3-methoxy- 4-amine
pyridin-4-yl)-propionamide SC_5006 CIS-3-[1-(Cyclobutyl-methyl)-8-
INT 998 6- SC_5003 521.3 dimethylamino-2-oxo-8-phenyl-1,3-
methoxypyridazin- diazaspiro[4.5]decan-3-yl]-N-(6-methoxy- 3-amine
pyridazin-3-yl)-propionamide SC_5007
CIS-3-[1-(Cyclobutyl-methyl)-8- INT 998 5- SC_5003 568.3
dimethylamino-2-oxo-8-phenyl-1,3- (methylsulfonyl)
diazaspiro[4.5]decan-3-yl]-N-(5- pyridin-2-amine
methylsulfonyl-pyridin-2-yl)- propionamide SC_5008
CIS-3-[1-(Cyclobutyl-methyl)-8- INT 998 5- SC_5003 520.3
dimethylamino-2-oxo-8-phenyl-1,3- methoxypyridin-
diazaspiro[4.5]decan-3-yl]-N-(5-methoxy- 2-amine
pyridin-2-yl)-propionamide SC_5009 CIS-3-[1-(Cyclobutyl-methyl)-8-
INT 998 6- SC_5003 568.3 dimethylamino-2-oxo-8-phenyl-1,3-
(methylsulfonyl) diazaspiro[4.5]decan-3-yl]-N-(6- pyridin-3-amine
methylsulfonyl-pyridin-3-yl)- propionamide SC_5010
CIS-3-[1-(Cyclobutyl-methyl)-8- INT 998 6- SC_5003 521.3
dimethylamino-2-oxo-8-phenyl-1,3- methoxypyrazin-
diazaspiro[4.5]decan-3-yl]-N-(6-methoxy- 2-amine
pyrazin-2-yl)-propionamide SC_5011 CIS-3-[1-(Cyclobutyl-methyl)-8-
INT 998 4- SC_5003 520.3 dimethylamino-2-oxo-8-phenyl-1,3-
methoxypyridin- diazaspiro[4.5]decan-3-yl]-N-(4-methoxy- 2-amine
pyridin-2-yl)-propionamide SC_5012 CIS-3-[1-(Cyclobutyl-methyl)-8-
INT 998 oxazol-5- SC_5003 494.3 dimethylamino-2-oxo-8-phenyl-1,3-
ylmethanamine diazaspiro[4.5]decan-3-yl]-N-(oxazol-5-yl-
methyl)-propionamide SC_5013 CIS-3-[1-(Cyclobutyl-methyl)-8- INT
998 oxazol-2- SC_5003 494.3 dimethylamino-2-oxo-8-phenyl-1,3-
ylmethanamine diazaspiro[4.5]decan-3-yl]-N-(oxazol-2-yl-
methyl)-propionamide SC_5014 CIS-1-(Cyclobutyl-methyl)-3-[3-[3,4-
INT 998 piperidine-3,4- SC_5003 513.3
dihydroxy-piperidin-1-yl]-3-oxo-propyl]- diol
8-dimethylamino-8-phenyl-1,3- diazaspiro[4.5]decan-2-one SC_5015
CIS-1-(Cyclobutyl-methyl)-3-[3-[3,4- INT 998 pyrrolidine-3,4-
SC_5003 499.3 dihydroxy-pyrrolidin-1-yl]-3-oxo-propyl]- diol
8-dimethylamino-8-phenyl-1,3- diazaspiro[4.5]decan-2-one SC_5016
CIS-1-(Cyclobutyl-methyl)-3-[3-[(3S,4R)- INT 998 (3S,4R)- SC_5003
499.3 3,4-dihydroxy-pyrrolidin-1-yl]-3-oxo- pyrrolidine-3,4-
propyl]-8-dimethylamino-8-phenyl-1,3- diol
diazaspiro[4.5]decan-2-one SC_5017 CIS-1-(Cyclobutyl-methyl)-8- INT
998 piperidin-3-ol SC_5003 497.3
dimethylamino-3-[3-(3-hydroxy-piperidin-
1-yl)-3-oxo-propyl]-8-phenyl-1,3- diazaspiro[4.5]decan-2-one
SC_5018 CIS-3-[1-(Cyclobutyl-methyl)-8- INT 998 1- SC_5003 497.3
dimethylamino-2-oxo-8-phenyl-1,3- (aminomethyl)cyclobutanol
diazaspiro[4.5]decan-3-yl]-N-[(1-hydroxy-
cyclobutyl)-methyl]-propionamide SC_5019
CIS-1-(Cyclobutyl-methyl)-8- INT 998 5,6,7,8- SC_5003 520.3
dimethylamino-3-[3-oxo-3-(5,6,7,8- tetrahydro-
tetrahydro-[1,2,4]triazolo[1,5-a]pyrazin-7- [1,2,4]triazolo[1,
yl)-propyl]-8-phenyl-1,3- 5-a]pyrazine diazaspiro[4.5]decan-2-one
SC_5020 CIS-3-[3-[1-(Cyclobutyl-methyl)-8- INT 998 3-amino-N,N-
SC_5003 512.4 dimethylamino-2-oxo-8-phenyl-1,3- dimethylpropanamide
diazaspiro[4.5]decan-3-yl]- propanoylamino]-N,N-dimethyl-
propionamide SC_5023 CIS-3-[8-Dimethylamino-1-[(1-hydroxy- SC_5002
2- SC_5022 507.3 cyclobutyl)-methyl]-2-oxo-8-phenyl-1,3-
bromopyrimidine diazaspiro[4.5]decan-3-yl]-N-pyrimidin-2-
yl-propionamide SC_5024 CIS-3-[8-Dimethylamino-1-[(1-hydroxy-
INT-899 2- SC_5055 523.3 cyclobutyl)-methyl]-2-oxo-8-phenyl-1,3-
aminopyrimidin- diazaspiro[4.5]decan-3-yl]-N-(4-hydroxy- 4(3H)-one
pyrimidin-2-yl)-propionamide SC_5025
CIS-3-[8-Dimethylamino-1-[(1-hydroxy- SC_5002 2-bromo-4- SC_5022
537.3 cyclobutyl)-methyl]-2-oxo-8-phenyl-1,3- methoxypyrimidine
diazaspiro[4.5]decan-3-yl]-N-(4-methoxy-
pyrimidin-2-yl)-propionamide SC_5026
CIS-3-[1-(Cyclobutyl-methyl)-8- SC_5046 -- SC_5059 427.3
methylamino-2-oxo-8-phenyl-1,3-
diazaspiro[4.5]decan-3-yl]-2,2-dimethyl- propionamide SC_5027
CIS-3-[1-[(1-Hydroxy-cyclobutyl)- SC_5054 -- SC_5059 459.3
methyl]-8-methylamino-2-oxo-8-phenyl-
1,3-diazaspiro[4.5]decan-3-yl]-N-(2- hydroxy-ethyl)-propionamide
SC_5028 CIS-3-[1-[(1-Hydroxy-cyclobutyl)- SC_5002 -- SC_5059 415.3
methyl]-8-methylamino-2-oxo-8-phenyl-
1,3-diazaspiro[4.5]decan-3-yl]- propionamide SC_5029
CIS-3-[1-[(1-Hydroxy-cyclobutyl)- SC_5052 -- SC_5059 429.3
methyl]-8-methylamino-2-oxo-8-phenyl-
1,3-diazaspiro[4.5]decan-3-yl]-N-methyl- propionamide SC_5030
CIS-3-[1-[(1-Hydroxy-cyclobutyl)- SC_5001 -- SC_5059 493.3
methyl]-8-methylamino-2-oxo-8-phenyl-
1,3-diazaspiro[4.5]decan-3-yl]-N- pyridazin-3-yl-propionamide
SC_5032 CIS-3-[8-Dimethylamino-1-(2-methoxy- INT 896 methylamine
SC_5031 417.3 ethyl)-2-oxo-8-phenyl-1,3-
diazaspiro[4.5]decan-3-yl]-N-methyl- propionamide SC_5033
CIS-3-[8-Dimethylamino-1-(2-methoxy- INT 896 pyrimidin-5- SC_5031
481.3 ethyl)-2-oxo-8-phenyl-1,3- amine
diazaspiro[4.5]decan-3-yl]-N-pyrimidin-5- yl-propionamide SC_5035
CIS-3-[8-Dimethylamino-1-(2-methoxy- INT-792 -- SC_5034 431.3
ethyl)-2-oxo-8-phenyl-1,3- diazaspiro[4.5]decan-3-yl]-2,2-dimethyl-
propionamide SC_5036 CIS-3-[8-Dimethylamino-1-[(1-hydroxy- INT 899
pyridin-3-amine SC_5055 506.3
cyclobutyl)-methyl]-2-oxo-8-phenyl-1,3-
diazaspiro[4.5]decan-3-yl]-N-pyridin-3-yl- propionamide SC_5037
CIS-3-[8-Dimethylamino-1-[(1-hydroxy- INT 899 pyridin-4-amine
SC_5055 506.3 cyclobutyl)-methyl]-2-oxo-8-phenyl-1,3-
diazaspiro[4.5]decan-3-yl]-N-pyridin-4-yl- propionamide SC_5038
CIS-2-[3-[8-Dimethylamino-1-(3- INT 896 2-amino-2- SC_5031 502.3
methoxy-propyl)-2-oxo-8-phenyl-1,3- methylpropanamide
diazaspiro[4.5]decan-3-yl]- propanoylamino]-2-methyl-propionamide
SC_5039 CIS-3-[8-Dimethylamino-1-(3-methoxy- INT 896 2- SC_5031
523.3 propyl)-2-oxo-8-phenyl-1,3- (methylsulfonyl)ethanamine
diazaspiro[4.5]decan-3-yl]-N-(2- methylsulfonyl-ethyl)-propionamide
SC_5040 CIS-3-[8-Dimethylamino-1-(3-methoxy- INT 896 2-aminoethanol
SC_5031 461.3 propyl)-2-oxo-8-phenyl-1,3-
diazaspiro[4.5]decan-3-yl]-N-(2-hydroxy- ethyl)-propionamide
SC_5041 CIS-8-Dimethylamino-1-(3-methoxy- INT 896 piperazin-2-one
SC_5031 500.3 propyl)-3-[3-oxo-3-(3-oxo-piperazin-1-yl)-
propyl]-8-phenyl-1,3- diazaspiro[4.5]decan-2-one SC_5042
CIS-(2R)-1-[3-[8-Dimethylamino-1-(3- INT 896 (R)-pyrrolidine-
SC_5031 514.3 methoxy-propyl)-2-oxo-8-phenyl-1,3- 2-carboxamide
diazaspiro[4.5]decan-3-yl]-propanoyl]- pyrrolidine-2-carboxylic
acid amide SC_5043 CIS-N-(Carbamoyl-methyl)-3-[8- INT 896 2-
SC_5031 474.3 dimethylamino-1-(3-methoxy-propyl)-2- aminoacetamide
oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3- yl]-propionamide SC_5044
CIS-3-[8-Dimethylamino-1-[(1-hydroxy- INT 899 pyridin-2-amine
SC_5055 506.3 cyclobutyl)-methyl]-2-oxo-8-phenyl-1,3-
diazaspiro[4.5]decan-3-yl]-N-pyridin-2-yl- propionamide SC_5045
CIS-3-[1-(Cyclobutyl-methyl)-8-(ethyl- INT-791 -- SC_5034 455.3
methyl-amino)-2-oxo-8-phenyl-1,3-
diazaspiro[4.5]decan-3-yl]-2,2-dimethyl- propionamide SC_5046
CIS-3-[1-(Cyclobutyl-methyl)-8- INT-897 -- SC_5034 441.3
dimethylamino-2-oxo-8-phenyl-1,3- product
diazaspiro[4.5]decan-3-yl]-2,2-dimethyl- step 1 propionamide
SC_5047 CIS-3-[1-(Cyclobutyl-methyl)-8- INT-898 NH.sub.4Cl SC_5031
413.3 dimethylamino-2-oxo-8-phenyl-1,3-
diazaspiro[4.5]decan-3-yl]-propionamide SC_5048
CIS-3-[1-(Cyclobutyl-methyl)-8-[methyl- INT 894 methylamine SC_5031
469.4 (2-methyl-propyl)-amino]-2-oxo-8-phenyl-
1,3-diazaspiro[4.5]decan-3-yl]-N-methyl- propionamide SC_5049
CIS-3-[1-(Cyclobutyl-methyl)-8- INT 898 methylamine SC_5031 427.3
dimethylamino-2-oxo-8-phenyl-1,3-
diazaspiro[4.5]decan-3-yl]-N-methyl- propionamide SC_5051
CIS-3-[8-Dimethylamino-1-[(1-hydroxy- INT 899 pyrimidin-5- SC_5055
507.3 cyclobutyl)-methyl]-2-oxo-8-phenyl-1,3- amine
diazaspiro[4.5]decan-3-yl]-N-pyrimidin-5- yl-propionamide SC_5052
CIS-3-[8-Dimethylamino-1-[(1-hydroxy- INT 899 methylamine SC_5055
443.3 cyclobutyl)-methyl]-2-oxo-8-phenyl-1,3-
diazaspiro[4.5]decan-3-yl]-N-methyl- propionamide SC_5053
CIS-3-[8-Dimethylamino-1-[(1-hydroxy- INT 899 2- SC_5055 487.3
cyclobutyl)-methyl]-2-oxo-8-phenyl-1,3- methoxyethanamine
diazaspiro[4.5]decan-3-yl]-N-(2-methoxy- ethyl)-propionamide
SC_5054 CIS-3-[8-Dimethylamino-1-[(1-hydroxy- INT 899
2-aminoethanol SC_5055 473.3
cyclobutyl)-methyl]-2-oxo-8-phenyl-1,3-
diazaspiro[4.5]decan-3-yl]-N-(2-hydroxy- ethyl)-propionamide
SC_5057 CIS-N-(Carbamoyl-methyl)-3-[1- SC_5056 -- SC_5059 484.3
(cyclobutyl-methyl)-8-methylamino-2-
oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-
yl]-2,2-dimethyl-propionamide SC_5058
CIS-3-[8-Dimethylamino-1-[(1-hydroxy- INT-790 -- SC_5034 457.3
cyclobutyl)-methyl]-2-oxo-8-phenyl-1,3-
diazaspiro[4.5]decan-3-yl]-2,2-dimethyl- propionamide SC_5060
CIS-3-[1-[(1-Hydroxy-cyclobutyl)- SC_5058 -- SC_5059 443.3
methyl]-8-methylamino-2-oxo-8-phenyl-
1,3-diazaspiro[4.5]decan-3-yl]-2,2- dimethyl-propionamide m/z in
analogy (M + Example Chemical name Reactant I Reactant II of method
.sup.1H NMR data H).sup.+ SC_5061* CIS-3-[8-(Ethyl- INT-797
3-bromo-2,2- step 1 of 1HNMR (DMSO-d6, 369.2 methyl-amino)-2-
dimethyl- INT-897 400 MHz, at 100.degree. C.), .delta.
oxo-8-phenyl-1,3- propionitrile (ppm) = 7.34-7.21 (m,
diazaspiro[4.5]decan- 5H), 6.70 (bs, 1H), 3-yl]-2,2-dimethyl- 3.28
(s, 2H), 3.19 (s, 2H), propionitrile 2.32-2.24 (m, 4H), 2.06 (s,
3H), 1.87-1.82 (m, 4H), 1.45-1.37 (bs, 2H), 1.27 (s, 6H), 0.93 (t,
3H, 6.8 Hz). SC_5062* CIS-3-(8- INT-976 3-bromo-2,2- step 1 of
1HNMR (DMSO-d6, 355.2 Dimethylamino-2- dimethyl- INT-897 400 MHz),
.delta. (ppm) = 7.35-7.24
(m, oxo-8-phenyl-1,3- propionitrile 5H), diazaspiro[4.5]decan- 7.03
(bs, 1H), 3.25 (s, 2H), 3-yl)-2,2-dimethyl- 3.15 (s, 2H), 2.32 (bs,
propionitrile 2H), 1.92 (s, 6H), 1.82 (bs, 4H), 1.38 (bs, 2H), 1.24
(s, 6H). SC_5064 CIS-3-[8-(Ethyl- SC_5061 SC_5034 1HNMR (DMSO-d6,
387.5 methyl-amino)-2- 400 MHz), .delta. (ppm) = 7.33-7.22 (m,
oxo-8-phenyl-1,3- 5H), diazaspiro[4.5]decan- 7.14 (bs, 1H),
6.83-6.79 (m, 3-yl]-2,2-dimethyl- 2H),3.07 (s, 2H), propionamide
3.01 (s, 2H), 2.32 (bs, 2H), 2.11 (bs, 2H), 1.96 (s, 3H), 1.78-1.69
(m, 4H), 1.31 (bs, 2H), 0.99 (s, 6H), 0.90 (t, 3H, J = 6.66 Hz).
SC_5065* CIS-3-[8-(Ethyl- SC_5061 methyl iodide step 1 of 1HNMR
(DMSO-d6, 383.2 methyl-amino)-1- INT-953 400 MHz), .delta. (ppm) =
7.34-722 (m, methyl-2-oxo-8- 5H), phenyl-1,3- 3.38 (s, 2H), 3.21
(s, 2H), diazaspiro[4.5]decan- 2.71-2.64 (m, 5H),
3-yl]-2,2-dimethyl- 2.19-2.16 (m, 4H), propionitrile 1.96 (s, 3H),
1.37-1.30 (m, 4H), 1.25 (s, 6H), 0.98 (t, 3H, J = 6.48 Hz). SC_5066
CIS-3-[8-(Ethyl- SC_5065 SC_5034 1HNMR (DMSO-d6, 401.2
methyl-amino)-1- 400 MHz), .delta. (ppm) = 7.34-723 (m,
methyl-2-oxo-8- 5H), phenyl-1,3- 7.15 (s, 1H), 6.90 (s, 1H),
diazaspiro[4.5]decan- 3.13 (s, 4H), 3-yl]-2,2-dimethyl- 2.67-2.60
(m, 5H), 2.12-2.09 (m, propionamide 4H), 1.95 (s, 3H), 1.33-1.25
(m, 4H), 1.01-0.97 (m, 9H). SC_5067 CIS-2,2-Dimethyl-3- SC_5063
SC_5034 1HNMR (DMSO-d6, 358.48 (8-methylamino-2- 400 MHz), .delta.
(ppm) = 7.42 (d, oxo-8-phenyl-1,3- 2H, J = 8),
diazaspiro[4.5]decan- 7.33-7.29 (t, 2H, J = 8), 3-yl)-propionamide
7.19-7.15 (m, 2H), 6.90 (s, 1H), 6.51 (bs, 1H), 3.12-3.09 (m, 4H),
1.90-1.83 (m, 7H), 1.74-1.69 (m, 2H), 1.41-1.38 (d, 2H, J = 12),
1.01 (s, 6H) SC_5068* CIS-3-(8- INT-1008 3-bromo-2,2- step 1 of
1HNMR (DMSO-d6, 355.1 Ethylamino-2-oxo-8- dimethyl- INT-897 400
MHz), .delta. (ppm) = 7.42 (d, phenyl-1,3- propionitrile 12H, J =
7.32 Hz), diazaspiro[4.5]decan- 7.30 (t, 2H, J = 7.20 Hz),
3-yl)-2,2-dimethyl- 7.17 (t, 1H, J = 7.12 Hz), propionitrile 6.78
(s, 1H), 3.35 (s, 2H), 3.17 (s, 2H), 2.05 (m, 7H), 1.67-1.43 (m,
4H), 1.25 (s, 6H), 0.91 (t, 3H, J = 6.78 Hz). SC_5069 CIS-3-(8-
SC_5068 SC_5034 1HNMR (DMSO-d6, 373.0 Ethylamino-2-oxo-8- 400 MHz,
at 100.degree. C.), .delta. phenyl-1,3- (ppm) = 7.45 (d, 2H, J =
6.52 Hz), diazaspiro[4.5]decan- 7.32 (t, 2H, 3-yl)-2,2-dimethyl- J
= 7.2 Hz), 7.21 (t, 1H, propionamide J = 6.66 Hz), 6.64 (bs, 2H),
6.18 (s, 1H), 3.16 (s, 4H), 2.19 (bs, 2H), 1.91-1.79 (m, 6H), 1.44
(bs, 2H), 1.07 (s, 6H), 0.95 (t, 3H, J = 6.62 Hz). SC_5070
CIS-3-(8- SC_5062 SC_5034 1HNMR(600 MHz, 373.3 Dimethylamino-2-
DMSO) .delta. oxo-8-phenyl-1,3- 7.39-7.29 (m, 4H),
diazaspiro[4.5]decan- 7.29-7.22 (m, 1H), 7.14 (s, 1H),
3-yl)-2,2-dimethyl- 6.81 (s, 1H), 6.76 (s, propionamidc 1H), 3.09
(s, 2H), 3.03 (s, 2H), 2.40-2.21 (m, 2H), 1.93 (s, 6H), 1.82 1.74
(m,2H), 1.74 1.61 (m, 2H), 1.37-1.29 (m, 2H), 1.01 (s, 6H). SC_5071
CIS-3-[1- SC_5068 cyclobutylmethylbromide step 1 of 1HNMR (DMSO-d6,
441.0 (Cyclobutyl- INT-953 (for 400 MHz), .delta. (ppm) = 7.42 (d,
methyl)-8- step 1), 2H, J = 7.48 Hz), ethylamino-2-oxo-8- SC_5034
(for 7.30 (t, 2H, J = 7.32 Hz), phenyl-1,3- step 2) 7.19-7.14 (m,
diazaspiro[4.5]decan- 2H), 6.94 (s, 1H), 3-yl]-2,2-dimethyl- 3.12
(s, 4H), 3.05 (d, 2H, J = 7.08 Hz), propionamide 2.14-2.03 (m, 4H),
1.95-1.88 (m, 4H), 1.79-1.66 (m, 4H), 1.53-1.25 (m, 4H), 1.01 (s,
6H), 0.95 (t, 3H). SC_5072 CIS-3-[8- SC_5062 toluene-4- step 1 of
1HNMR (DMSO-d6, 443.3 Dimethylamino-1- sulfonic acid INT-953 (for
400 MHz), .delta. (ppm) = 7.37-7.24 (m, (oxetan-3-yl- oxetan-3-
step 1), 5H), methyl)-2-oxo-8- ylmethyl ester SC_5034 (for 7.14 (s,
1H), 6.92 (s, 1H), phenyl-1,3- step 2) 4.62-4.58 (m, 2H),
diazaspiro[4.5]decan- 4.35 (t, 2H, J = 6.02 Hz),
3-yl]-2,2-dimethyl- 3.29 (d, 2H, J = 7.28 Hz), propionamide
3.14-3.08 (m, 5H), 2.68-2.65 (m, 2H), 2.01-1.95 (m, 8H), 1.33-1.22
(m, 4H), 1.00 (s, 6H). SC_5073 CIS-3-[1- SC_5075 SC_5034 1HNMR
(DMSO-d6, 427.4 (Cyclopropyl- 400 MHz), .delta. (ppm) = 7.35-7.25
(m, methyl)-8- 5H), dimethylamino-2- 7.15 (s, 1H), 6.90 (s, 1H),
oxo-8-phenyl-1,3- 3.13 (s, 4H), 2.90 (d, diazaspiro[4.5]decan- 2H,
J = 6.32 Hz), 3-yl]-2,2-dimethyl- 2.68-2.65 (m, 2H), propionamide
2.15-2.09 (m 2H), 1.98 (s, 6H), 1.36-1.23 (m, 4H), 1.01 (s, 6H),
0.91 (m, 1H), 0.44 (d, 2H, J = 6.84 Hz), 0.24 (d, 2H, J = 4.08 Hz).
SC_5076 CIS-8- INT-1075 morpholine SC_5031 527.5 Dimethylamino-3-
(2,2-dimethyl-3- morpholin-4-yl-3- oxo-propyl)-1-[(1- hydroxy-
cyclobutyl)-methyl]- 8-phenyl-1,3- diazaspiro[4.5]decan- 2-one
SC_5077 CIS-3-[8- INT-1075 2- SC_5031 1HNMR (DMSO-d6, 501.2
Dimethylamino-1- aminoethanol 400 MHz at 100.degree. C.), .delta.
[(1-hydroxy- (ppm) = 7.33-7.18 (m, cyclobutyl)-methyl]- 6H), 5.66
(bs, 1H), 2-oxo-8-phenyl-1,3- 4.19 (bs, 1H), 3.40 (bs, 2H),
diazaspiro[4.5]decan- 3.25-3.22 (m, 4H), 3-yl]-N-(2-hydroxy- 3.13
(bs, 4H), 2.62-2.59 (m, ethyl)-2,2-dimethyl- 2H), 2.10-2.05 (m,
9H), propionamide 1.91-1.89 (m, 2H), 1.70-1.66 (m, 2H), 1.41-1.28
(m, 4H), 1.09 (s, 6H). SC_5078 CIS-3-[1-[(1-Cyano- SC_5062
toluene-4- step 1 of .sup.1HNMR (DMSO-d.sub.6, 466.2
cyclobutyl)-methyl]- sulfonic acid INT-953 (for 400 MHz), .delta.
(ppm) = 7.37-7.31 (m, 8-dimethylamino-2- 1-cyano- step 1), 4H),
oxo-8-phenyl-1,3- cyclobutylmethyl SC_5034 (for 7.27-7.23 (m, 1H),
diazaspiro[4.5]decan- ester step 2) 7.14 (s, 1H),
3-yl]-2,2-dimethyl- 6.93 (s, 1H), 3.32 (s, 2H), propionamide 3.17
(s, 4 H), 2.69-2.65 (d, 2H), 2.45-2.38 (m, 2H), 2.35-2.28 (m, 2H),
2.0-1.95 (m, 10H), 1.41-1.38 (d, 2H), 1.30-1.23 (t, 2H), 1.02 (s,
6H). SC_5080* TRANS-3-[1- INT-1059 3-bromo-2,2- step 1 of 1HNMR at
20.degree. C. 409.2 (Cyclopropyl- dimethyl- INT-897 (for (DMSO-d6,
400 MHz), methyl)-8- propionitrile step 1), step .delta. (ppm) =
7.44-7.28 (m, dimethylamino-2- (step 1), 1 of INT-953 5H), 3.46 (s,
2H), oxo-8-phenyl-1,3- cyclopropylmethylbromide (for step 2) 3.23
(s, 2H), diazaspiro[4.5]decan- (step 2) 2.72-2.66 (m, 2H),
2.57-2.55 (m, 3-yl]-2,2-dimethyl- 2H), 1.91 (s, 6H), propionitrile
1.55-1.45 (m, 6H), 1.27 (s, 6H), 0.51 (bs, 1H), 0.19-0.14 (m, 2H),
(-0.22)-(-0.26) (m, 2H). SC_5081 TRANS-3-[8- INT-1059 3-bromo-2,2-
step 1 of 1HNMR (DMSO-d6, 457.2 Dimethylamino-1- dimethyl- INT-897
(for 400 MHz), .delta. (ppm) = 7.43-7.27 (m, [(1-hydroxy-
propionitrile step 1), 5H), cyclobutyl)-methyl]- (step 1), 1-
SC_5074 (for 7.21 (bs, 1H), 7.05 (bs, 1H), 2-oxo-8-phenyl-1,3-
oxaspiro[2.3]hexane steps 2 and 5.75 (s, 1H), 3.17 (s,
diazaspiro[4.5]decan- (step 2) 3) 2H), 2.67-2.65 (bs,
3-yl]-2,2-dimethyl- 2H), 2.55 (s, 2H), propionamide 1.91 (s, 6H),
1.73-1.68 (m, 4H), 1.48-1.34 (m, 7H), 1.04 (s, 6H), 0.90-0.83 (m,
1H). SC_5082 TRANS-3-(8- INT-1061 3-bromo-2,2- step 1 of 1HNMR at
100.degree. C. 373.3 Dimethylamino-2- dimethyl- INT-897 (for
(DMSO-d6, 400 MHz), oxo-8-phenyl-1,3- propionitrile step 1),
.delta. (ppm) = 7.37-7.25 (m, diazaspiro[4.5]decan- (step 1)
SC_5034 (for 5H), 6.68 (bs, 2H), 3-yl)-2,2-dimethyl- step 2) 6.30
(bs, 1H), 3.22 (s, propionamide 2H), 3.17 (s, 2H), 2.16 (bs, 2H),
1.99 (bs, 8H), 1.70-1.68 (m, 2H), 1.43-1.38 (m, 2H), 1.09 (s, 6H).
SC_5084 CIS-3-[1- INT-1031 2-cyano-2- SC_5075 1H NMR (DMSO-d6):
445.3 (Cyclopropyl- methylpropyl (step 1), .delta. 7.41-7.36 (m,
1H), methyl)-8- 4- SC_5034 7.18-7.07 (m, 4H), dimethylamino-8-(3-
methylbenzenesulfonate (step 2) 6.89 (br, s, 1H), 3.14 (s,
fluorophenyl)-2-oxo- (step 1) 4H), 2.90 (d, 2H), 1,3- 2.64 (d, 2H),
2.11 (t, 2H), diazaspiro[4.5]decan- 1.98 (s, 6H), 1.34 (d,
3-yl]-2,2-dimethyl- 2H), 1.27 (t, 2H), propionamide 1.02 (s, 6H),
0.93-0.88 (m, 1H), 0.47-0.42 (m, 2H), 0.26-0.22 (m, 2H). SC_5085
CIS-1-((1- INT-983 (1- step 1 of 425.3 (cyclopropylmethyl)-
cyanocyclopropyl)methyl INT-897 (for 8-(dimethylamino)- 4- step 1),
2-oxo-8-phenyl-1,3- methylbenzenesulfonate SC_5034 (for
diazaspiro[4.5]decan- (step 1) step 2) 3-yl)methyl)
cyclopropanecarboxamide SC_5086 CIS-3-((1- INT-983 (3- step 1 of
441.3 (cyclopropylmethyl)- cyanooxetan- INT-897 (for
8-(dimethylamino)- 3-yl)methyl 4- step 1), 2-oxo-8-phenyl-1,3-
methylbenzenesulfonate SC_5034 (for diazaspiro[4.5]decan- (step 1)
step 2) 3- yl)methyl)oxetane-3- carboxamide SC_5087 CIS-3-(1-
SC_5073 step 2 of 413.3 (cyclopropylmethyl)- SC_5063
8-(methylamino)-2- oxo-8-phenyl-1,3- diazaspiro[4.5]decan-
3-yl)-2,2- dimethylpropanamide SC_5088 CIS-3-(1- INT-983 3- step 1
of (cyclopropylmethyl)- bromopropane INT-897 (for
8-(dimethylamino)- nitrile step 1), 2-oxo-8-phenyl-1,3- SC_5034
(for diazaspiro[4.5]decan- step 2) 3-yl)propanamide SC_5089
CIS-3-(8- INT-976 3-bromo-2,2- step 1 of (dimethylamino)-1-
dimethyl- INT-897 (for ((1- propionitrile step 1), step
fluorocyclopropyl)methyl)- (step 1), (1- 1 of INT-953 2-oxo-8-
fluorocyclopropyl)methyl (for step 2), phenyl-1,3- 4- SC_5034 (for
diazaspiro[4.5]decan- methylbenzenesulfonate step 3) 3-yl)-2,2-
(step 2), dimethylpropanamide H2O2 nitrile hydrolysis (step 3)
(*comparative examples)
[0331] The chemical structures of the example compounds are shown
in the following table.
TABLE-US-00004 ##STR00115## SC_5001 ##STR00116## SC_5002
##STR00117## SC_5003 ##STR00118## SC_5004 ##STR00119## SC_5005
##STR00120## SC_5006 ##STR00121## SC_5007 ##STR00122## SC_5008
##STR00123## SC_5009 ##STR00124## SC_5010 ##STR00125## SC_5011
##STR00126## SC_5012 ##STR00127## SC_5013 ##STR00128## SC_5014
##STR00129## SC_5015 ##STR00130## SC_5016 ##STR00131## SC_5017
##STR00132## SC_5018 ##STR00133## SC_5019 ##STR00134## SC_5020
##STR00135## SC_5022 ##STR00136## SC_5023 ##STR00137## SC_5024
##STR00138## SC_5025 ##STR00139## SC_5026 ##STR00140## SC_5027
##STR00141## SC_5028 ##STR00142## SC_5029 ##STR00143## SC_5030
##STR00144## SC_5031 ##STR00145## SC_5032 ##STR00146## SC_5033
##STR00147## SC_5034 ##STR00148## SC_5035 ##STR00149## SC_5036
##STR00150## SC_5037 ##STR00151## SC_5038 ##STR00152## SC_5039
##STR00153## SC_5040 ##STR00154## SC_5041 ##STR00155## SC_5042
##STR00156## SC_5043 ##STR00157## SC_5044 ##STR00158## SC_5045
##STR00159## SC_5046 ##STR00160## SC_5047 ##STR00161## SC_5048
##STR00162## SC_5049 ##STR00163## SC_5051 ##STR00164## SC_5052
##STR00165## SC_5053 ##STR00166## SC_5054 ##STR00167## SC_5055
##STR00168## SC_5056 ##STR00169## SC_5057 ##STR00170## SC_5058
##STR00171## SC_5059 ##STR00172## SC_5060 ##STR00173## SC_5061*
##STR00174## SC_5062* ##STR00175## SC_5063* ##STR00176## SC_5064
##STR00177## SC_5065* ##STR00178## SC_5066 ##STR00179## SC_5067
##STR00180## SC_5068* ##STR00181## SC_5069 ##STR00182## SC_5070
##STR00183## SC_5071 ##STR00184## SC_5072 ##STR00185## SC_5073
##STR00186## SC_5074 ##STR00187## SC_5075* ##STR00188## SC_5076
##STR00189## SC_5077 ##STR00190## SC_5078 ##STR00191## SC_5079
##STR00192## SC_5080* ##STR00193## SC_5081 ##STR00194## SC_5082
##STR00195## SC_5083 ##STR00196## SC_5084 ##STR00197## SC_5085
##STR00198## SC_5086 ##STR00199## SC_5087 ##STR00200## SC_5088
##STR00201## SC_5089 (*comparative examples)
[0332] Pharmacological Investigations
[0333] Functional investigation on the human mu-opioid receptor
(hMOP), human kappa-opioid receptor (hKOP), human delta-opioid
receptor (hDOP), and human nociceptin/orphanin FQ peptide receptor
(hNOP)
[0334] Human Mu-Opioid Peptide (hMOP) Receptor Binding Assay
[0335] The hMOP receptor binding assay was performed as homogeneous
SPA-assay (scintillation proximity assay) using the assay buffer 50
mM TRIS-HCl (pH 7.4) supplemented with 0.052 mg/ml bovine serum
albumin (Sigma-Aldrich Co. St. Louis. Mo.). The final assay volume
(250 .mu.l/well) included 1 nM of [N-allyl-2.3-.sup.3H]naloxone as
ligand (PerkinElmer Life Sciences. Inc. Boston. Mass. USA). and
either test compound in dilution series or 25 .mu.M unlabelled
naloxone for determination of unspecific binding. The test compound
was diluted with 25% DMSO in H.sub.2O to yield a final 0.5% DMSO
concentration. which also served as a respective vehicle control.
The assay was started by adding wheat germ agglutinin coated SPA
beads (GE Healthcare UK Ltd. Buckinghamshire. UK) which had been
preloaded with hMOP receptor membranes (PerkinElmer Life Sciences.
Inc. Boston. Mass. USA). After incubation for 90 minutes at RT and
centrifugation for 20 minutes at 500 rpm the signal rate was
measured by means of a 1450 Microbeta Trilux .beta.-counter
(PerkinElmer Life Sciences/Wallac. Turku. Finland). Half-maximal
inhibitory concentration (IC50) values reflecting 50% displacement
of [.sup.3H]naloxone-specific receptor binding were calculated by
nonlinear regression analysis and Ki values were calculated by
using the Cheng-Prusoff equation. (Cheng and Prusoff. 1973).
[0336] Human Kappa-Opioid Peptide (hKOP) Receptor Binding Assay
[0337] The hKOP receptor binding assay is run as homogeneous
SPA-assay (scintillation proximity assay) using the assay buffer 50
mM TRIS-HCl (pH 7.4) supplemented with 0.076 mg BSA/ml. The final
assay volume of 250 .mu.l per well includes 2 nM of
[.sup.3H]U69,593 as ligand, and either test compound in dilution
series or 100 .mu.M unlabelled naloxone for determination of
unspecific binding. The test compound is diluted with 25% DMSO in
H.sub.2O to yield a final 0.5% DMSO concentration which serves as
respective vehicle control, as well. The assays are started by the
addition of wheat germ agglutinin coated SPA beads (1 mg SPA
beads/250 .mu.l final assay volume per well) which has been
preloaded for 15 minutes at room temperature with hKOP receptor
membranes (14.8 .mu.g/250 .mu.l final assay volume per well). After
short mixing on a mini-shaker, the microtiter plates are covered
with a lid and the assay plates are incubated for 90 minutes at
room temperature. After this incubation, the microtiter plates are
sealed with a topseal and centrifuged for 20 minutes at 500 rpm.
The signal rate is measured after a short delay of 5 minutes by
means of a 1450 Microbeta Trilux .beta.-counter (PerkinElmer Life
Sciences/Wallac, Turku, Finland). Half-maximal inhibitory
concentration (IC50) values reflecting 50% displacement of
[.sup.3H]U69.593-specific receptor binding are calculated by
nonlinear regression analysis and K; values are calculated by using
the Cheng-Prusoff equation, (Cheng and Prusoff, 1973).
[0338] Human Delta-Opioid Peptide (hDOP) Receptor Binding Assay
[0339] The hDOP receptor binding assay is performed as homogeneous
SPA-assay using the assay buffer 50 mM TRIS-HCl, 5 mM MgCl.sub.2
(pH 7.4). The final assay volume (250 l/well) includes 1 nM of
[Tyrosyl-3,5-.sup.3H]2-D-Ala-deltorphin II as ligand, and either
test compound in dilution series or 10 .mu.M unlabelled naloxone
for determination of unspecific binding. The test compound is
diluted with 25% DMSO in H.sub.2O to yield a final 0.5% DMSO
concentration which serves as respective vehicle control, as well.
The assays are started by the addition of wheat germ agglutinin
coated SPA beads (1 mg SPA beads/250 .mu.l final assay volume per
well) which has been preloaded for 15 minutes at room temperature
with hDOP receptor membranes (15.2 .mu.g/250 .mu.l final assay
volume per well). After short mixing on a mini-shaker, the
microtiter plates are covered with a lid and the assay plates are
incubated for 120 minutes at room temperature and centrifuged for
20 minutes at 500 rpm. The signal rate is measured by means of a
1450 Microbeta Trilux .beta.-counter (PerkinElmer Life
Sciences/Wallac, Turku, Finland). Half-maximal inhibitory
concentration (IC50) values reflecting 50% displacement of
[Tyrosyl-3,5-.sup.3H]2-D-Ala-deltorphin II-specific receptor
binding are calculated by nonlinear regression analysis and Ki
values are calculated by using the Cheng-Prusoff equation, (Cheng
and Prusoff, 1973).
[0340] Human Nociceptin/Orphanin FQ Peptide (hNOP) Receptor Binding
Assay
[0341] The hNOP receptor binding assay was performed as homogeneous
SPA-assay (scintillation proximity assay) using the assay buffer 50
mM TRIS-HCl. 10 mM MgCl.sub.2. 1 mM EDTA (pH 7.4). The final assay
volume (250 .mu.l/well) included 0.5 nM of
[leucyl-.sup.3H]nociceptin as ligand (PerkinElmer Life Sciences.
Inc. Boston. Mass. USA). and either test compound in dilution
series or 1 .mu.M unlabelled nociceptin for determination of
unspecific binding. The test compound was diluted with 25% DMSO in
H.sub.2O to yield a final 0.5% DMSO concentration. which also
served as a respective vehicle control. The assay was started by
adding wheat germ agglutinin coated SPA beads (GE Healthcare UK
Ltd. Buckinghamshire. UK) which had been preloaded with hMOP
receptor membranes (PerkinElmer Life Sciences. Inc. Boston. Mass.
USA). After incubation for 60 minutes at RT and centrifugation for
20 minutes at 500 rpm the signal rate was measured by means of a
1450 Microbeta Trilux .beta.-counter (PerkinElmer Life
Sciences/Wallac. Turku. Finland). Half-maximal inhibitory
concentration (IC50) values reflecting 50% displacement of
[.sup.3H]nociceptin-specific receptor binding were calculated by
nonlinear regression analysis and Ki values were calculated by
using the Cheng-Prusoff equation. (Cheng and Prusoff. 1973).
TABLE-US-00005 hNOP hMOP Example Ki [nM] Ki [nM] SC_5001 4 410
SC_5002 12.2 118 SC_5003 2.6 44.5 SC_5004 1.1 10 SC_5005 1.2 46.5
SC_5006 1.9 24.5 SC_5007 2.1 66 SC_5008 1 25 SC_5009 1.8 43.5
SC_5010 2.2 19 SC_5011 2.6 51.5 SC_5012 5.8 28 SC_5013 3.6 8.2
SC_5014 6.6 33 SC_5015 10.6 24.5 SC_5016 11.4 31 SC_5017 2.6 7.6
SC_5018 3.2 1.7 SC_5019 3 49 SC_5020 8.1 47.5 SC_5022 3.1 99.5
SC_5023 14.5 245 SC_5024 9.4 160 SC_5025 22.5 130 SC_5026 17.5 555
SC_5027 215 1195 SC_5028 140 895 SC_5029 205 1635 SC_5030 20 810
SC_5031 195 510 SC_5032 220 1130 SC_5033 48.5 1030 SC_5034 130 1185
SC_5035 230 815 SC_5036 4.2 140 SC_5037 8 40 SC_5038 72.5 175
SC_5039 130.5 130 SC_5040 115.5 395 SC_5041 63.5 445 SC_5042 70.5
190 SC_5043 101 210 SC_5044 5.6 160.5 SC_5045 19 910 SC_5046 1
113.4 SC_5047 5.8 69 SC_5048 1195 4146.7 SC_5049 1.5 11.3 SC_5051
3.6 320 SC_5052 12 250 SC_5053 16.5 58.5 SC_5054 18.5 160 SC_5055
11.5 74 SC_5056 7.4 64 SC_5057 75.5 124 SC_5058 19.5 545 SC_5059
111.5 88.5 SC_5060 285 1300 SC_5064 3% @1 .mu.M 3% @1 .mu.M (DOP
20%) SC_5066 0% @1 .mu.M 7% @1 .mu.M (DOP 22%) SC_5067 1300 11% @1
.mu.M SC_5069 1% @1 .mu.M 7% @1 .mu.M (KOP 50%) SC_5070 245 7340
SC_5071 625 2845 SC_5072 150 4675 SC_5073 23 480 SC_5074 260 2615
SC_5076 7 670 SC_5077 15 485 SC_5078 0.5 180 SC_5079 12 510 SC_5081
815 4025 SC_5082 340 790 SC_5083 22 610 SC_5084 12 2475
[0342] Protocol for [.sup.35S]GTP.gamma.S Functional
NOP/MOP/KOP/DOP Assays
[0343] Cell membrane preparations of CHO-K1 cells transfected with
the human MOP receptor (Art.-No. RBHOMM) or the human DOP receptor
(Art.-No.RBHODM), and HEK293 cells transfected with the human NOP
receptor (Art.-No.RBHORLM) or the human KOP receptor (Art.-No.
6110558) are available from PerkinElmer (Waltham, Mass.). Membranes
from CHO-K1 cells transfected with the human nociceptin/orphanin FQ
peptide (hNOP) receptor (Art.-No. 93-0264C2, DiscoveRx Corporation,
Freemont, Calif.) are also used. [.sup.35S]GTP.gamma.S (Art.-No.
NEG030H; Lot-No. #0112, #0913, #1113 calibrated to 46.25 TBq/mmol)
is available from PerkinElmer (Waltham, Mass.).
[0344] The [.sup.35S]GTP.gamma.S assays are carried out essentially
as described by Gillen et al (2000). They are run as homogeneous
scintillation proximity (SPA) assays in microtiter luminescence
plates, where each well contains 1.5 mg of WGA-coated SPA-beads. To
test the agonistic activity of test compounds on recombinant hNOP,
hMOP, hDOP, and hKOP receptor expressing cell membranes from CHO-K1
or HEK293 cells, 10 or 5 .mu.g membrane protein per assay are
incubated with 0.4 nM [.sup.35S]GTP.gamma.S and serial
concentrations of receptor-specific agonists in buffer containing
20 mM HEPES pH 7.4, 100 mM NaCl, 10 mM MgCl.sub.2, 1 mM EDTA, 1 mM
dithiothreitol, 1.28 mM NaN.sub.3, and 10 .mu.M GDP for 45 min at
room temperature. The microtiter plates are then centrifuged for 10
min at 830 to sediment the SPA beads. The microtiter plates are
sealed and the bound radioactivity [cpm] is determined after a
delay of 15 min by means of a 1450 Microbeta Trilux (PerkinElmer,
Waltham, Mass.).
[0345] The unstimulated basal binding activity (UBS.sub.obs [cpm])
is determined from 12 unstimulated incubates and is set as 100%
basal binding. For determination of the potency and the efficacy,
the arithmetic mean of the observed total [.sup.35S]GTP.gamma.S
binding (TB.sub.obs [cpm]) of all incubates (duplicates) stimulated
by the receptor-specific agonists (i.e. N/OFQ, SNC80, DAMGO, or
U69,593) are transformed in percent total binding (TB.sub.obs [%])
relative to the basal binding activity (i.e. 100% binding). The
potency (EC.sub.50) of the respective agonist and its maximal
achievable total [.sup.35S]GTP.gamma.S binding (TB.sub.calc [%])
above its calculated basal binding (UBS.sub.calc [%]) are
determined from its transformed data (TB.sub.obs [%]) by means of
nonlinear regression analysis with XLfit for each individual
concentration series. Then the difference between the calculated
unstimulated [.sup.35S]GTP.gamma.S binding (UBS.sub.calc [%]) and
the maximal achievable total [.sup.35S]GTP.gamma.S binding
(TB.sub.calc [%]) by each tested agonist is determined (i.e.
B1.sub.calc [%]). This difference (B1.sub.calc [%]) as a measure of
the maximal achievable enhancement of [.sup.35S]GTP.gamma.S binding
by a given agonist is used to calculate the relative efficacy of
test compounds versus the maximal achievable enhancement by a
receptor-specific full agonist, e.g. N/OFQ (B1.sub.calc-N/OFQ [%])
which is set as 100% relative efficacy for the hNOP receptor.
Likewise, the percentage efficacies of test compounds at the hDOP,
hMOP, or hKOP receptor are determined versus the calculated maximal
enhancement of [.sup.35S]GTP.gamma.S binding by the full agonists
SNC80 (B1.sub.calc-SNC80 [%]), DAMGO (B1.sub.calc-DAMGO [%]) and
U69,593 (B1.sub.calc-U69,593 [%]) which are set as 100% relative
efficacy at each receptor, respectively.
[0346] The foregoing description and examples have been set forth
merely to illustrate the invention and are not intended to be
limiting. Since modifications of the described embodiments
incorporating the spirit and substance of the invention may occur
to persons skilled in the art, the invention should be construed
broadly to include all variations within the scope of the appended
claims and equivalents thereof.
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