U.S. patent application number 16/207916 was filed with the patent office on 2019-04-04 for 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 Ruth JOSTOCK, Achim KLESS, Thomas KOCH, Rene Michael KOENIGS, Sven KUEHNERT, Klaus LINZ, Paul RATCLIFFE, Wolfgang SCHROEDER, Anita WEGERT.
Application Number | 20190100515 16/207916 |
Document ID | / |
Family ID | 55129636 |
Filed Date | 2019-04-04 |
View All Diagrams
United States Patent
Application |
20190100515 |
Kind Code |
A1 |
KUEHNERT; Sven ; et
al. |
April 4, 2019 |
8-AMINO-2-OXO-1,3-DIAZA-SPIRO-[4.5]-DECANE DERIVATIVES
Abstract
The invention relates to
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) ;
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: |
55129636 |
Appl. No.: |
16/207916 |
Filed: |
December 3, 2018 |
Related U.S. Patent Documents
|
|
|
|
|
|
Application
Number |
Filing Date |
Patent Number |
|
|
15984995 |
May 21, 2018 |
|
|
|
16207916 |
|
|
|
|
15405627 |
Jan 13, 2017 |
|
|
|
15984995 |
|
|
|
|
Current U.S.
Class: |
1/1 |
Current CPC
Class: |
C07D 401/04 20130101;
C07D 405/06 20130101; C07D 235/02 20130101; A61P 29/00 20180101;
C07D 405/04 20130101; A61P 25/04 20180101; C07D 401/14 20130101;
C07D 409/06 20130101; C07D 401/06 20130101; A61P 25/00 20180101;
C07D 409/04 20130101; C07D 403/06 20130101 |
International
Class: |
C07D 409/06 20060101
C07D409/06; C07D 403/06 20060101 C07D403/06; C07D 401/04 20060101
C07D401/04; C07D 401/06 20060101 C07D401/06; C07D 401/14 20060101
C07D401/14; C07D 235/02 20060101 C07D235/02; C07D 405/04 20060101
C07D405/04; C07D 405/06 20060101 C07D405/06; C07D 409/04 20060101
C07D409/04 |
Foreign Application Data
Date |
Code |
Application Number |
Jan 13, 2016 |
EP |
16 151 015.1 |
Claims
1. A compound according to general formula (I) ##STR00147## 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
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;
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--; 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; or a moiety
according to general formula (X); ##STR00148## 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; 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.6-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.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.
3. 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.
4. 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.
5. 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.
6. 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--.
7. 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.
8. The compound according to claim 1, wherein R.sup.3 means a
6-14-membered aryl moiety, unsubstituted, mono- or
polysubstituted.
9. The compound according to claim 1, wherein R.sup.3 means a
5-14-membered heteroaryl moiety, unsubstituted, mono- or
polysubstituted.
10. The compound according to claim 1, wherein R.sup.4 means
--H.
11. 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.
12. 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.
13. 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.
14. 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.
15. 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.
16. The compound according to claim 1, wherein R.sup.5 means
--H.
17. 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 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,
--O--C.sub.1-C.sub.4-alkyl, --O--(CH.sub.2CH.sub.2--O).sub.1-30--H,
--O--(CH.sub.2CH.sub.2--O).sub.1-30--CH.sub.3, --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.
18. The compound according to claim 1, wherein R.sup.5 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, --C.sub.1-C.sub.4-alkyl-OH,
--O--C.sub.1-C.sub.4-alkyl, --O--(CH.sub.2CH.sub.2--O).sub.1-30--H,
--O--(CH.sub.2CH.sub.2--O).sub.1-30--CH.sub.3, --C(.dbd.O)OH,
--C(.dbd.O)C.sub.1-C.sub.4-alkyl,
--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, --NH.sub.2,
--NHC.sub.1-C.sub.4-alkyl, N(C.sub.1-C.sub.4-alkyl).sub.2,
--NHC(.dbd.O)--C.sub.1-C.sub.4-alkyl,
--NC.sub.1-C.sub.4-alkylC(.dbd.O)C.sub.1-C.sub.4-alkyl,
--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 optionally connected through
--C.sub.1-C.sub.6-alkylene-, linear or branched, saturated or
unsaturated, unsubstituted.
19. The compound according to claim 1, wherein R.sup.5 means 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, --CN, --OH,
--C.sub.1-C.sub.4-alkyl, --C.sub.1-C.sub.4-alkyl-OH,
--O--C.sub.1-C.sub.4-alkyl, --O--(CH.sub.2CH.sub.2--O).sub.1-30--H,
--O--(CH.sub.2CH.sub.2--O).sub.1-30--CH.sub.3, --C(.dbd.O)OH,
--C(.dbd.O)C.sub.1-C.sub.4-alkyl,
--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, --NH.sub.2,
--NHC.sub.1-C.sub.4-alkyl, N(C.sub.1-C.sub.4-alkyl).sub.2,
--NHC(.dbd.O)--C.sub.1-C.sub.4-alkyl,
--NC.sub.1-C.sub.4-alkylC(.dbd.O)C.sub.1-C.sub.4-alkyl,
--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
heterocycloalkyl moiety is optionally connected through
--C.sub.1-C.sub.6-alkylene-, linear or branched, saturated or
unsaturated, unsubstituted.
20. The compound according to claim 1, which has a structure
according to any of general formulas (II-A) to (VIII-C):
##STR00149## ##STR00150## ##STR00151## wherein in each case
R.sup.1, R.sup.2, R.sup.3, R.sup.4, and R.sup.5 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.
21. The compound according to claim 1, wherein R.sup.5 is selected
from the group consisting of: ##STR00152## ##STR00153##
##STR00154##
22. 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; or 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, .dbd.O,
--S(.dbd.O).sub.2--C.sub.1-C.sub.4-alkyl 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; 3-12-membered heterocycloalkyl,
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, and --O--C.sub.1-C.sub.4-alkyl; wherein said 3-12-membered
heterocycloalkyl is optionally connected through
--C.sub.1-C.sub.6-alkylene-, unsubstituted or substituted with
.dbd.O; 6-14-membered aryl, 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 6-14-membered
aryl is optionally connected through --C.sub.1-C.sub.6-alkylene- or
--S(.dbd.O).sub.2--; 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, .dbd.O, --OH, --O--C.sub.1-C.sub.4-alkyl,
--O--(CH.sub.2CH.sub.2--O).sub.1-30--H,
--O--(CH.sub.2CH.sub.2--O).sub.1-30--CH.sub.3, --C(.dbd.O)OH,
--C(.dbd.O)C.sub.1-C.sub.4-alkyl,
--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,
--S(.dbd.O).sub.2C.sub.1-C.sub.4-alkyl, --NH.sub.2,
--NH--C.sub.1-C.sub.4-alkyl, --N(C.sub.1-C.sub.4-alkyl).sub.2,
--NHC(.dbd.O)--C.sub.1-C.sub.4-alkyl,
--NH--S(.dbd.O).sub.2C.sub.1-C.sub.4-alkyl; or 3-12-membered
cycloalkyl, 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, .dbd.O, --OH, --C.sub.1-C.sub.4-alkyl,
--C.sub.1-C.sub.4-alkyl-OH, --NH.sub.2,
--NH--C.sub.1-C.sub.4-alkyl, --N(C.sub.1-C.sub.4-alkyl).sub.2,
--NHC(.dbd.O)--C.sub.1-C.sub.4-alkyl,
--NHS(.dbd.O).sub.2--C.sub.1-C.sub.4-alkyl,
--O--C.sub.1-C.sub.4-alkyl, --O--(CH.sub.2CH.sub.2--O).sub.1-30--H,
--O--(CH.sub.2CH.sub.2--O).sub.1-30--CH.sub.3, --C(.dbd.O)OH,
--C(.dbd.O)OC.sub.1-C.sub.4-alkyl,
--C(.dbd.O)C.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,
--S(.dbd.O).sub.2C.sub.1-C.sub.4-alkyl, -phenyl,
--C(.dbd.O)-phenyl, --C(.dbd.O)-pyridyl, -pyridyl, -thiazolyl,
--N-methyldiazolyl, -pyrimidinyl, and -pyridazinyl; 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 3-12-membered heterocycloalkyl,
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,
.dbd.O, --OH, --C.sub.1-C.sub.4-alkyl, --NH.sub.2,
--NH--C.sub.1-C.sub.4-alkyl, --N(C.sub.1-C.sub.4-alkyl).sub.2,
--NHC(.dbd.O)--C.sub.1-C.sub.4-alkyl,
--NHS(.dbd.O).sub.2--C.sub.1-C.sub.4-alkyl,
--O--C.sub.1-C.sub.4-alkyl, --O--(CH.sub.2CH.sub.2--O).sub.1-30--H,
--O--(CH.sub.2CH.sub.2--O).sub.1-30--CH.sub.3, --C(.dbd.O)OH,
--C(.dbd.O)OC.sub.1-C.sub.4-alkyl,
--C(.dbd.O)C.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,
--S(.dbd.O).sub.2C.sub.1-C.sub.4-alkyl, -phenyl,
--C(.dbd.O)-phenyl, --C(.dbd.O)-pyridyl, -pyridyl, -thiazolyl,
--N-methyldiazolyl, -pyrimidinyl, and -pyridazinyl; 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; and 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.
23. The compound according to claim 1, which has a structure
according to general formula (I') ##STR00155## wherein R.sup.1 to
R.sup.5, R.sup.10 to R.sup.20 are defined as in claim 1, or a
physiologically acceptable salt thereof.
24. The compound according to claim 1, which has a structure
according to general formula (IX) ##STR00156## wherein R.sup.C
means --H or --OH; R.sup.3 means -phenyl or -3-fluorophenyl;
R.sup.5 means C.sub.1-C.sub.6-alkyl, linear or branched, saturated,
unsubstituted or monosubstituted with --OH, --CN, --NH.sub.2,
--NHC(.dbd.O)C.sub.1-C.sub.4-alkyl,
--NHS(.dbd.O).sub.2--C.sub.1-C.sub.4-alkyl, or
--S(.dbd.O).sub.2--C.sub.1-C.sub.4-alkyl; or 3-6-membered
heterocycloalkyl, saturated, unsubstituted or substituted with
--OH; wherein said 3-6-membered heterocycloalkyl is optionally
connected through --CH.sub.2-- or --(CH.sub.2).sub.2--; or a
physiologically acceptable salt thereof.
25. The compound according to claim 24, wherein the 3-6-membered
heterocycloalkyl is selected from the group consisting of oxetanly,
tetrahydrofuranyl and tetrahydropyranyl.
26. The compound according to claim 1, which is selected from the
group consisting of
CIS-4-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspir-
o[4.5]decan-3-yl]-butyramide;
CIS-1-(Cyclobutyl-methyl)-8-dimethylamino-3-[2-[2-[2-[2-[2-(2-methoxy-eth-
oxy)-ethoxy]-ethoxy]-ethoxy]-ethoxy]-ethyl]-8-phenyl-1,3-diazaspiro[4.5]de-
can-2-one;
CIS-1-(Cyclobutyl-methyl)-8-dimethylamino-3-[2-[2-(2-methoxy-et-
hoxy)-ethoxy]-ethyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;
CIS-1-(Cyclobutyl-methyl)-8-dimethylamino-3-[2-[2-[2-[2-[2-[2-(2-methoxy--
ethoxy)-ethoxy]-ethoxy]-ethoxy]-ethoxy]-ethoxy]-ethyl]-8-phenyl-1,3-diazas-
piro[4.5]decan-2-one;
CIS-1-(Cyclobutyl-methyl)-8-dimethylamino-3-[2-[2-[2-[2-(2-methoxy-ethoxy-
)-ethoxy]-ethoxy]-ethoxy]-ethyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;
CIS-1-(Cyclobutyl-methyl)-8-dimethylamino-3-[2-(2-methoxy-ethoxy)-ethyl]--
8-phenyl-1,3-diazaspiro[4.5]decan-2-one;
CIS-1-(Cyclobutyl-methyl)-8-dimethylamino-3-(2-methoxy-ethyl)-8-phenyl-1,-
3-diazaspiro[4.5]decan-2-one;
CIS-1-(Cyclobutyl-methyl)-8-dimethylamino-3-[2-[2-[2-(2-methoxy-ethoxy)-e-
thoxy]-ethoxy]-ethyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;
CIS-1-(Cyclobutyl-methyl)-8-dimethylamino-3-(2-methylsulfonyl-ethyl)-8-ph-
enyl-1,3-diazaspiro[4.5]decan-2-one;
CIS-1-(Cyclobutyl-methyl)-8-methylamino-3-(2-methylsulfonyl-ethyl)-8-phen-
yl-1,3-diazaspiro[4.5]decan-2-one;
CIS-8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-3-(2-methylsulfonyl-
-ethyl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;
CIS-4-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspir-
o[4.5]decan-3-yl]-butyronitrile;
CIS-4-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspir-
o[4.5]decan-3-yl]-N-methyl-butyramide;
CIS-3-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspir-
o[4.5]decan-3-yl]-2,2-dimethyl-propionitrile;
CIS-1-(Cyclobutyl-methyl)-8-dimethylamino-3-[2-[2-[2-[2-[2-[2-[2-(2-metho-
xy-ethoxy)-ethoxy]-ethoxy]-ethoxy]-ethoxy]-ethoxy]-ethoxy]-ethyl]-8-phenyl-
-1,3-diazaspiro[4.5]decan-2-one;
CIS-1-(Cyclobutyl-methyl)-8-dimethylamino-3-methyl-8-phenyl-1,3-diazaspir-
o[4.5]decan-2-one;
CIS-1-[(1-Hydroxy-cyclobutyl)-methyl]-8-methylamino-3-(2-methylsulfonyl-e-
thyl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;
CIS-3-[1-[(1-Hydroxy-cyclobutyl)-methyl]-8-methylamino-2-oxo-8-phenyl-1,3-
-diazaspiro[4.5]decan-3-yl]-propionitrile;
CIS-2-[1-[(1-Hydroxy-cyclobutyl)-methyl]-8-methylamino-2-oxo-8-phenyl-1,3-
-diazaspiro[4.5]decan-3-yl]-acetonitrile;
CIS-8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-8-phenyl-3-(tetrahy-
dro-pyran-4-yl-methyl)-1,3-diazaspiro[4.5]decan-2-one;
CIS-8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-3-(2-morpholin-4-yl-
-ethyl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;
CIS-3-(3-Chloro-propyl)-1-(cyclobutyl-methyl)-8-dimethylamino-8-phenyl-1,-
3-diazaspiro[4.5]decan-2-one;
CIS-4-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspir-
o[4.5]decan-3-yl]-butyric acid methyl ester;
CIS-3-[8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-2-oxo-8-phenyl-1-
,3-diazaspiro[4.5]decan-3-yl]-propionitrile;
CIS-2-[8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-2-oxo-8-phenyl-1-
,3-diazaspiro[4.5]decan-3-yl]-acetonitrile;
CIS-3-Acetyl-8-dimethylamino-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;
CIS-8-Dimethylamino-3-(2-methylsulfonyl-ethyl)-8-phenyl-1,3-diazaspiro[4.-
5]decan-2-one
CIS-1-Acetyl-8-dimethylamino-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;
CIS-1-(Cyclopropyl-methyl)-8-dimethylamino-3-(2-methylsulfonyl-ethyl)-8-p-
henyl-1,3-diazaspiro[4.5]decan-2-one;
CIS-8-Dimethylamino-3-(2-methylsulfonyl-ethyl)-1-(oxetan-3-yl-methyl)-8-p-
henyl-1,3-diazaspiro[4.5]decan-2-one;
CIS-8-Dimethylamino-1-(3-methoxy-propyl)-3-(2-methylsulfonyl-ethyl)-8-phe-
nyl-1,3-diazaspiro[4.5]decan-2-one;
CIS-8-Dimethylamino-8-phenyl-1-(p-tolylsulfonyl)-1,3-diazaspiro[4.5]decan-
-2-one;
CIS-8-Dimethylamino-3-[(1,1-dioxo-thian-4-yl)-methyl]-1-[(1-hydrox-
y-cyclobutyl)-methyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;
CIS-1-(Cyclobutyl-methyl)-8-dimethylamino-3-[(4-hydroxy-tetrahydro-pyran--
4-yl)-methyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;
CIS-1-(Cyclopropyl-methyl)-8-dimethylamino-8-phenyl-3-tetrahydro-pyran-4--
yl-1,3-diazaspiro[4.5]decan-2-one;
CIS-1-(Cyclobutyl-methyl)-8-dimethylamino-3-[(4-hydroxy-1,1-dioxo-thian-4-
-yl)-methyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;
CIS-8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-8-phenyl-3-tetrahyd-
ro-pyran-4-yl-1,3-diazaspiro[4.5]decan-2-one;
CIS-1-[[9-Dimethylamino-3-(2-methylsulfonyl-ethyl)-2-oxo-8-1,3-diazaspiro-
[4.5]-decan-1-yl]-methyl]-cyclobutane-1-carbonitrile;
CIS-8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-3-[(4-hydroxy-tetra-
hydro-pyran-4-yl)-methyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;
CIS-8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-3-[(4-hydroxy-1,1-d-
ioxo-thian-4-yl)-methyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;
CIS-1-(Cyclopropyl-methyl)-8-dimethylamino-3-(1,1-dioxo-thian-4-yl)-8-phe-
nyl-1,3-diazaspiro[4.5]decan-2-one;
CIS-8-Dimethylamino-3-(1,1-dioxo-thian-4-yl)-1-[(1-hydroxy-cyclobutyl)-me-
thyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;
CIS-3-(1-Acetyl-piperidin-4-yl)-1-(cyclopropyl-methyl)-8-dimethylamino-8--
phenyl-1,3-diazaspiro[4.5]decan-2-one;
CIS-3-(1-Benzoyl-piperidin-4-yl)-1-(cyclopropyl-methyl)-8-dimethylamino-8-
-phenyl-1,3-diazaspiro[4.5]decan-2-one;
CIS-1-(Cyclopropyl-methyl)-8-dimethylamino-8-phenyl-3-[1-(pyridine-4-carb-
onyl)-piperidin-4-yl]-1,3-diazaspiro[4.5]decan-2-one;
CIS-1-(Cyclopropyl-methyl)-8-dimethylamino-3-[(4-hydroxy-tetrahydro-pyran-
-4-yl)-methyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;
CIS-1-(Cyclobutyl-methyl)-8-dimethylamino-3-[2-(4-hydroxy-tetrahydro-pyra-
n-4-yl)-ethyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;
CIS-3-[(1-Acetyl-piperidin-4-yl)-methyl]-1-(cyclopropyl-methyl)-8-dimethy-
lamino-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;
CIS-1-(Cyclopropyl-methyl)-8-dimethylamino-8-phenyl-3-piperidin-4-yl-1,3--
diazaspiro[4.5]decan-2-one;
CIS-1-(Cyclopropyl-methyl)-8-dimethylamino-3-(2-hydroxy-2-methyl-propyl)--
8-phenyl-1,3-diazaspiro[4.5]decan-2-one;
CIS-1-(Cyclopropyl-methyl)-8-dimethylamino-8-phenyl-3-(1-pyrimidin-5-yl-p-
iperidin-4-yl)-1,3-diazaspiro[4.5]decan-2-one;
CIS-1-(Cyclopropyl-methyl)-8-dimethylamino-8-phenyl-3-(1-phenyl-piperidin-
-4-yl)-1,3-diazaspiro[4.5]decan-2-one;
CIS-1-(Cyclopropyl-methyl)-8-dimethylamino-8-phenyl-3-(piperidin-4-yl-met-
hyl)-1,3-diazaspiro[4.5]decan-2-one;
CIS-3-(1-Benzoyl-piperidin-4-yl)-8-dimethylamino-8-phenyl-1,3-diazaspiro[-
4.5]decan-2-one
CIS-8-Dimethylamino-8-phenyl-3-[1-(pyridine-4-carbonyl)-piperidin-4-yl]-1-
,3-diazaspiro[4.5]decan-2-one;
CIS-3-(1-Acetyl-piperidin-4-yl)-8-dimethylamino-8-phenyl-1,3-diazaspiro[4-
.5]decan-2-one;
CIS-1-(Cyclopropyl-methyl)-8-dimethylamino-3-[(4-hydroxy-1,1-dioxo-thian--
4-yl)-methyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;
CIS-8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-3-(2-hydroxy-2-meth-
yl-propyl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one; and the
physiologically acceptable salts thereof.
27. The compound according to claim 1 for use in the treatment of
pain.
28. A medicament comprising a compound according to claim 1.
29. A compound according to general formula (IIIa) or (IIIb),
##STR00157## wherein R.sup.1, R.sup.2 and R.sup.3 are defined as in
claim 1; and PG is a protecting group; or a physiologically
acceptable salt thereof.
30. A method of treating pain in a patient in need thereof, said
method comprising administering to said patient an effective amount
therefor of at least one compound according to claim 1.
Description
[0001] This application is a continuation of U.S. Nonprovisional
patent application Ser. No. 15/984,995, filed May 21, 2018,
pending, which is a continuation of U.S. Nonprovisional patent
application Ser. No. 15/405,627, filed Jan. 13, 2017, now
abandoned, which claims foreign priority benefit under 35 U.S.C.
.sctn. 119 of European Patent Application No. 16 151 015.1, filed
Jan. 13, 2016, the disclosures of which are incorporated herein by
reference.
[0002] The invention relates to
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
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 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--; 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; or a moiety
according to general formula (X);
##STR00002##
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; 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;
[0020] --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.
[0021] 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.
[0022] 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.
[0023] In preferred embodiments of the compound according to the
invention, 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;
preferably --H.
[0024] 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.
[0025] 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.
[0026] 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--.
[0027] In yet another preferred embodiment, [0028] --R means --H or
--CH.sub.3; and [0029] --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.
[0030] 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.
[0031] 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 poly-substituted. 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.
[0032] 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 poly-substituted. More preferably, R.sup.3
means -thienyl, -pyridinyl, -imidazolyl or benzimidazolyl, in each
case unsubstituted or monosubstituted with --F, --Cl or
--CH.sub.3.
[0033] In a preferred embodiment of the compound according to the
invention, R.sup.4 means --H.
[0034] 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.
[0035] 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--.
[0036] 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--.
[0037] 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--.
[0038] 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--.
[0039] In a preferred embodiment of the compound according to the
invention, R.sup.5 means --H.
[0040] 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 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, --O--C.sub.1-C.sub.4-alkyl,
--O--(CH.sub.2CH.sub.2--O).sub.1-30--H,
--O--(CH.sub.2CH.sub.2--O).sub.1-30--CH.sub.3, --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. Preferably, R.sup.5 means
--C.sub.1-C.sub.6-alkyl, linear or branched, saturated or
unsaturated, unsubstituted or monosubstituted with --F, --Cl, --Br,
--I, --CN, --OH, --O--C.sub.1-C.sub.4-alkyl,
--O--(CH.sub.2CH.sub.2--O).sub.1-30--H,
--O--(CH.sub.2CH.sub.2--O).sub.1-30--CH.sub.3, --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 or
--S(.dbd.O).sub.2C.sub.1-C.sub.4-alkyl.
[0041] More preferably, [0042] (i) R.sup.5 means
--C.sub.1-C.sub.6-alkyl, linear or branched, saturated or
unsaturated, unsubstituted or monosubstituted with --F, --Cl, --Br,
--I, --CN, --OH, --O--C.sub.1-C.sub.4-alkyl,
--O--(CH.sub.2CH.sub.2--O).sub.1-30--H,
--O--(CH.sub.2CH.sub.2--O).sub.1-30--CH.sub.3,
--S(.dbd.O)C.sub.1-C.sub.4-alkyl or
--S(.dbd.O).sub.2C.sub.1-C.sub.4-alkyl; or [0043] (ii) R.sup.5
means --C.sub.3-C.sub.6-alkyl, linear or branched, saturated or
unsaturated, monosubstituted with --C(.dbd.O)NH.sub.2,
--C(.dbd.O)NHC.sub.1-C.sub.4-alkyl, or
--C(.dbd.O)N(C.sub.1-C.sub.4-alkyl).sub.2.
[0044] In another preferred embodiment of the compound according to
the invention, R.sup.5 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.sub.1-C.sub.4-alkyl-OH, --O--(CH.sub.2CH.sub.2--O).sub.1-30--H,
--O--(CH.sub.2CH.sub.2--O).sub.1-30--CH.sub.3, --C(.dbd.O)OH,
--C(.dbd.O)C.sub.1-C.sub.4-alkyl,
--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, --NH.sub.2,
--NHC.sub.1-C.sub.4-alkyl, N(C.sub.1-C.sub.4-alkyl).sub.2,
--NHC(.dbd.O)--C.sub.1-C.sub.4-alkyl,
--N(C.sub.1-C.sub.4-alkyl)C(.dbd.O)C.sub.1-C.sub.4-alkyl,
--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 optionally connected through
--C.sub.1-C.sub.6-alkylene-, linear or branched, saturated or
unsaturated, unsubstituted.
[0045] In a preferred embodiment of the compound according to the
invention, R.sup.5 means 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, --CN,
--OH, --C.sub.1-C.sub.4-alkyl, --O--C.sub.1-C.sub.4-alkyl,
--C.sub.1-C.sub.4-alkyl-OH, --O--(CH.sub.2CH.sub.2--O).sub.1-30--H,
--O--(CH.sub.2CH.sub.2--O).sub.1-30--CH.sub.3, --C(.dbd.O)OH,
--C(.dbd.O)C.sub.1-C.sub.4-alkyl,
--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, --NH.sub.2,
--NHC.sub.1-C.sub.4-alkyl, N(C.sub.1-C.sub.4-alkyl).sub.2,
--NHC(.dbd.O)--C.sub.1-C.sub.4-alkyl,
--N(C.sub.1-C.sub.4-alkyl)C(.dbd.O)C.sub.1-C.sub.4-alkyl,
--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
heterocycloalkyl moiety is optionally connected through
--C.sub.1-C.sub.6-alkylene-, linear or branched, saturated or
unsaturated, unsubstituted. Preferably, R.sup.5 means -oxetanyl,
-tetrahydrofuranyl, -tetrahydropyranyl, -piperidinyl, -piperazinyl,
-morpholinyl or -thiomorpholinyl, 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, -tetrahydropyranyl, -piperidinyl, -piperazinyl,
-morpholinyl or -thiomorpholinyl is connected through --CH.sub.2--
or --CH.sub.2CH.sub.2--.
[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, .dbd.O, --OH,
--O--C.sub.1-C.sub.4-alkyl, --O--(CH.sub.2CH.sub.2--O).sub.1-30--H,
--O--(CH.sub.2CH.sub.2--O).sub.1-30--CH.sub.3, --C(.dbd.O)OH,
--C(.dbd.O)C.sub.1-C.sub.4-alkyl,
--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,
--S(.dbd.O).sub.2C.sub.1-C.sub.4-alkyl, --NH.sub.2,
--NH--C.sub.1-C.sub.4-alkyl, --N(C.sub.1-C.sub.4-alkyl).sub.2,
--NHC(.dbd.O)--C.sub.1-C.sub.4-alkyl,
--NH--S(.dbd.O).sub.2C.sub.1-C.sub.4-alkyl; or 3-12-membered
cycloalkyl, 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, .dbd.O, --OH, --C.sub.1-C.sub.4-alkyl,
--C.sub.1-C.sub.4-alkyl-OH, --NH.sub.2,
--NH--C.sub.1-C.sub.4-alkyl, --N(C.sub.1-C.sub.4-alkyl).sub.2,
--NHC(.dbd.O)--C.sub.1-C.sub.4-alkyl,
--NHS(.dbd.O).sub.2--C.sub.1-C.sub.4-alkyl,
--O--C.sub.1-C.sub.4-alkyl, --O--(CH.sub.2CH.sub.2--O).sub.1-30--H,
--O--(CH.sub.2CH.sub.2--O).sub.1-30--CH.sub.3, --C(.dbd.O)OH,
--C(.dbd.O)OC.sub.1-C.sub.4-alkyl,
--C(.dbd.O)C.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,
--S(.dbd.O).sub.2C.sub.1-C.sub.4-alkyl, -phenyl,
--C(.dbd.O)-phenyl, --C(.dbd.O)-pyridyl, -thiazolyl,
--N-methyldiazolyl, -pyridyl, -pyrimidinyl, and -pyridazinyl;
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 3-12-membered
heterocycloalkyl, 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, .dbd.O, --OH, --C.sub.1-C.sub.4-alkyl,
--C.sub.1-C.sub.4-alkyl-OH, --NH.sub.2,
--NH--C.sub.1-C.sub.4-alkyl, --N(C.sub.1-C.sub.4-alkyl).sub.2,
--NHC(.dbd.O)--C.sub.1-C.sub.4-alkyl,
--NHS(.dbd.O).sub.2--C.sub.1-C.sub.4-alkyl,
--O--C.sub.1-C.sub.4-alkyl, --O--(CH.sub.2CH.sub.2--O).sub.1-30--H,
--O--(CH.sub.2CH.sub.2--O).sub.1-30--CH.sub.3, --C(.dbd.O)OH,
--C(.dbd.O)OC.sub.1-C.sub.4-alkyl,
--C(.dbd.O)C.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,
--S(.dbd.O).sub.2C.sub.1-C.sub.4-alkyl, -phenyl,
--C(.dbd.O)-phenyl, --C(.dbd.O)-pyridyl, -thiazolyl,
--N-methyldiazolyl, -pyridyl, -pyrimidinyl, and -pyridazinyl;
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.
[0048] In preferred embodiments, the compound according to the
invention has a structure according to any of general formulas
(II-A) to (VIII-C):
##STR00003## ##STR00004## ##STR00005##
wherein in each case R.sup.1, R.sup.2, R.sup.3, R.sup.4, and
R.sup.5 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.
[0049] Preferably, in the compounds according to general formula
(I) or any of the compounds according to general formulas (II-A) to
(VIII-C), R.sup.5 is selected from the group consisting of:
##STR00006## ##STR00007## ##STR00008##
[0050] In a particularly preferred embodiment of the compound
according to the invention
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; or R.sup.4 means
--H;
[0051] --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, .dbd.O,
--S(.dbd.O).sub.2--C.sub.1-C.sub.4-alkyl 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; 3-12-membered heterocycloalkyl,
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, and --O--C.sub.1-C.sub.4-alkyl; wherein said 3-12-membered
heterocycloalkyl is optionally connected through
--C.sub.1-C.sub.6-alkylene-, unsubstituted or substituted with
.dbd.O; 6-14-membered aryl, 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 6-14-membered
aryl is optionally connected through --C.sub.1-C.sub.6-alkylene- or
--S(.dbd.O).sub.2--; R.sup.5 means
--H;
[0052] --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, .dbd.O, --OH,
--O--C.sub.1-C.sub.4-alkyl, --O--(CH.sub.2CH.sub.2--O).sub.1-30--H,
--O--(CH.sub.2CH.sub.2--O).sub.1-30--CH.sub.3, --C(.dbd.O)OH,
--C(.dbd.O)C.sub.1-C.sub.4-alkyl,
--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,
--S(.dbd.O).sub.2C.sub.1-C.sub.4-alkyl, --NH.sub.2,
--NH--C.sub.1-C.sub.4-alkyl, --N(C.sub.1-C.sub.4-alkyl).sub.2,
--NHC(.dbd.O)--C.sub.1-C.sub.4-alkyl,
--NH--S(.dbd.O).sub.2C.sub.1-C.sub.4-alkyl; or 3-12-membered
heterocycloalkyl, 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, .dbd.O, --OH, --C.sub.1-C.sub.4-alkyl, --NH.sub.2,
--NH--C.sub.1-C.sub.4-alkyl, --N(C.sub.1-C.sub.4-alkyl).sub.2,
--NHC(.dbd.O)--C.sub.1-C.sub.4-alkyl,
--NHS(.dbd.O).sub.2--C.sub.1-C.sub.4-alkyl,
--O--C.sub.1-C.sub.4-alkyl, --O--(CH.sub.2CH.sub.2--O).sub.1-30--H,
--O--(CH.sub.2CH.sub.2--O).sub.1-30--CH.sub.3, --C(.dbd.O)OH,
--C(.dbd.O)OC.sub.1-C.sub.4-alkyl,
--C(.dbd.O)C.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,
--S(.dbd.O).sub.2C.sub.1-C.sub.4-alkyl, -phenyl,
--C(.dbd.O)-phenyl, --C(.dbd.O)-pyridyl, -pyridyl, -pyrimidinyl,
and -pyridazinyl; 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; and
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.
[0053] In a particularly preferred embodiment 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;
[0054] --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--; R.sup.5 means
--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,
--O--C.sub.1-C.sub.4-alkyl, --O--(CH.sub.2CH.sub.2--O).sub.1-30--H,
--O--(CH.sub.2CH.sub.2--O).sub.1-30--CH.sub.3, --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; preferably, R.sup.5 means
--C.sub.1-C.sub.6-alkyl, linear or branched, saturated or
unsaturated, unsubstituted or monosubstituted with --F, --Cl, --Br,
--I, --CN, --OH, --O--C.sub.1-C.sub.4-alkyl,
--O--(CH.sub.2CH.sub.2--O).sub.1-30--H,
--O--(CH.sub.2CH.sub.2--O).sub.1-30--CH.sub.3, --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 or
--S(.dbd.O).sub.2C.sub.1-C.sub.4-alkyl; or 3-12-membered
heterocycloalkyl, 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, --O--(CH.sub.2CH.sub.2--O).sub.1-30--H,
--O--(CH.sub.2CH.sub.2--O).sub.1-30--CH.sub.3, --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
heterocycloalkyl moiety is optionally connected through
--C.sub.1-C.sub.6-alkylene-, linear or branched, saturated or
unsaturated, unsubstituted; preferably, R.sup.5 means -oxetanyl,
-tetrahydrofuranyl, -tetrahydropyranyl, -piperidinyl, -piperazinyl,
-morpholinyl or -thiomorpholinyl, 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, -tetrahydropyranyl, -piperidinyl, -piperazinyl,
-morpholinyl or -thiomorpholinyl is connected through --CH.sub.2--
or --CH.sub.2CH.sub.2--; and 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.
[0055] Preferred compounds according to the invention are selected
from the group consisting of:
TABLE-US-00001 SC_4001
CIS-4-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-
phenyl-1,3-diazaspiro[4.5]decan-3-yl]-butyramide SC_4002
CIS-1-(Cyclobutyl-methyl)-8-dimethylamino-3-
[2-[2-[2-[2-[2-(2-methoxy-ethoxy)-ethoxy]-ethoxy]-ethoxy]-
ethoxy]-ethyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one SC_4003
CIS-1-(Cyclobutyl-methyl)-8-dimethylamino-
3-[2-[2-(2-methoxy-ethoxy)-ethoxy]-
ethyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one SC_4004
CIS-1-(Cyclobutyl-methyl)-8-dimethylamino-
3-[2-[2-[2-[2-[2-(2-methoxy-ethoxy)-ethoxy]-ethoxy]-
ethoxy]-ethoxy]-ethoxy]-ethyl]-8-phenyl-1,3-
diazaspiro[4.5]decan-2-one SC_4005
CIS-1-(Cyclobutyl-methyl)-8-dimethylamino-
3-[2-[2-[2-[2-(2-methoxy-ethoxy)-ethoxy]-ethoxy]-
ethoxy]-ethyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one SC_4006
CIS-1-(Cyclobutyl-methyl)-8-dimethylamino-
3-[2-(2-methoxy-ethoxy)-ethyl]-8-
phenyl-1,3-diazaspiro[4.5]decan-2-one SC_4007
CIS-1-(Cyclobutyl-methyl)-8-dimethylamino-3-
(2-methoxy-ethyl)-8-phenyl-1,3- diazaspiro[4.5]decan-2-one SC_4008
CIS-1-(Cyclobutyl-methyl)-8-dimethylamino-
3-[2-[2-[2-(2-methoxy-ethoxy)-ethoxy]-ethoxy]-
ethyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one SC_4009
CIS-1-(Cyclobutyl-methyl)-8-dimethylamino-
3-(2-methylsulfonyl-ethyl)-8-phenyl- 1,3-diazaspiro[4.5]decan-2-one
SC_4010 CIS-1-(Cyclobutyl-methyl)-8-methylamino-
3-(2-methylsulfonyl-ethyl)-8-phenyl- 1,3-diazaspiro[4.5]decan-2-one
SC_4011 CIS-8-Dimethylamino-1-[(1-hydroxy-
cyclobutyl)-methyl]-3-(2-methylsulfonyl-
ethyl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one SC_4012
CIS-4-[1-(Cyclobutyl-methyl)-8- dimethylamino-2-oxo-8-phenyl-1,3-
diazaspiro[4.5]decan-3-yl]-butyronitrile SC_4013
CIS-4-[1-(Cyclobutyl-methyl)-8- dimethylamino-2-oxo-8-phenyl-1,3-
diazaspiro[4.5]decan-3-yl]-N-methyl-butyramide SC_4014
CIS-3-[1-(Cyclobutyl-methyl)-8-dimethylamino-
2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-
3-yl]-2,2-dimethyl-propionitrile SC_4017
CIS-1-(Cyclobutyl-methyl)-8-dimethylamino-
3-[2-[2-[2-[2-[2-[2-[2-(2-methoxy-
ethoxy)-ethoxy]-ethoxy]-ethoxy]-ethoxy]-
ethoxy]-ethoxy]-ethyl]-8-phenyl-1,3- diazaspiro[4.5]decan-2-one
SC_4018 CIS-1-(Cyclobutyl-methyl)-8-
dimethylamino-3-methyl-8-phenyl-1,3- diazaspiro[4.5]decan-2-one
SC_4021 CIS-1-[(1-Hydroxy-cyclobutyl)-methyl]-
8-methylamino-3-(2-methylsulfonyl-
ethyl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one SC_4022
CIS-3-[1-[(1-Hydroxy-cyclobutyl)-methyl]-8-
methylamino-2-oxo-8-phenyl-1,3-
diazaspiro[4.5]decan-3-yl]-propionitrile SC_4024
CIS-2-[1-[(1-Hydroxy-cyclobutyl)-methyl]-
8-methylamino-2-oxo-8-phenyl-1,3-
diazaspiro[4.5]decan-3-yl]-acetonitrile SC_4025
CIS-8-Dimethylamino-1-[(1-hydroxy-
cyclobutyl)-methyl]-8-phenyl-3-(tetrahydro-
pyran-4-yl-methyl)-1,3-diazaspiro[4.5]decan-2-one SC_4026
CIS-8-Dimethylamino-1-[(1-hydroxy-
cyclobutyl)-methyl]-3-(2-morpholin-4-yl-
ethyl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one SC_4027
CIS-3-(3-Chloro-propyl)-1-(cyclobutyl-
methyl)-8-dimethylamino-8-phenyl-1,3- diazaspiro[4.5]decan-2-one
SC_4028 CIS-4-[1-(Cyclobutyl-methyl)-8-
dimethylamino-2-oxo-8-phenyl-1,3-
diazaspiro[4.5]decan-3-yl]-butyric acid methyl ester SC_4029
CIS-3-[8-Dimethylamino-1-[(1-hydroxy-
cyclobutyl)-methyl]-2-oxo-8-phenyl-1,3-
diazaspiro[4.5]decan-3-yl]-propionitrile SC_4030
CIS-2-[8-Dimethylamino-1-[(1-hydroxy-
cyclobutyl)-methyl]-2-oxo-8-phenyl-1,3-
diazaspiro[4.5]decan-3-yl]-acetonitrile SC_4031
CIS-3-Acetyl-8-dimethylamino-8-
phenyl-1,3-diazaspiro[4.5]decan-2-one SC_4032
CIS-8-Dimethylamino-3-(2-methylsulfonyl-ethyl)-
8-phenyl-1,3-diazaspiro[4.5]decan-2-one SC_4033
CIS-1-Acetyl-8-dimethylamino-8-phenyl-
1,3-diazaspiro[4.5]decan-2-one SC_4034
CIS-1-(Cyclopropyl-methyl)-8-
dimethylamino-3-(2-methylsulfonyl-ethyl)-8-
phenyl-1,3-diazaspiro[4.5]decan-2-one SC_4035
CIS-8-Dimethylamino-3-(2-methylsulfonyl-
ethyl)-1-(oxetan-3-yl-methyl)-8-
phenyl-1,3-diazaspiro[4.5]decan-2-one SC_4036
CIS-8-Dimethylamino-1-(3-methoxy-propyl)-
3-(2-methylsulfonyl-ethyl)-8-phenyl- 1,3-diazaspiro[4.5]decan-2-one
SC_4037 CIS-8-Dimethylamino-8-phenyl-1-(p-
tolylsulfonyl)-1,3-diazaspiro[4.5]decan-2-one SC_4038
CIS-8-Dimethylamino-3-[(1,1-dioxo-thian-4-yl)-
methyl]-1-[(1-hydroxy-cyclobutyl)-methyl]-
8-phenyl-1,3-diazaspiro[4.5]decan-2-one SC_4039
CIS-1-(Cyclobutyl-methyl)-8-dimethylamino-
3-[(4-hydroxy-tetrahydro-pyran-4-
yl)-methyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one SC_4040
CIS-1-(Cyclopropyl-methyl)-8-dimethylamino-
8-phenyl-3-tetrahydro-pyran-4-yl- 1,3-diazaspiro[4.5]decan-2-one
SC_4041 CIS-1-(Cyclobutyl-methyl)-8-dimethylamino-
3-[(4-hydroxy-1,1-dioxo-thian-4-yl)-
methyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one SC_4042
CIS-8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-
methyl]-8-phenyl-3-tetrahydro-
pyran-4-yl-1,3-diazaspiro[4.5]decan-2-one SC_4043
CIS-1-[[8-Dimethylamino-3-(2-methylsulfonyl-
ethyl)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-
1-yl]-methyl]-cyclobutane-1-carbonitrile SC_4044
CIS-8-Dimethylamino-1-[(1-hydroxy-
cyclobutyl)-methyl]-3-[(4-hydroxy-tetrahydro-pyran-
4-yl)-methyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one SC_4045
CIS-8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-
methyl]-3-[(4-hydroxy-1,1-dioxo-thian-4-yl)-
methyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one SC_4046
CIS-1-(Cyclopropyl-methyl)-8-dimethylamino-
3-(1,1-dioxo-thian-4-yl)-8-phenyl- 1,3-diazaspiro[4.5]decan-2-one
SC_4047 CIS-8-Dimethylamino-3-(1,1-dioxo-
thian-4-yl)-1-[(1-hydroxy-cyclobutyl)-
methyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one SC_4048
CIS-3-(1-Acetyl-piperidin-4-yl)-1-
(cyclopropyl-methyl)-8-dimethylamino-8-
phenyl-1,3-diazaspiro[4.5]decan-2-one SC_4049
CIS-3-(1-Benzoyl-piperidin-4-yl)-1-
(cyclopropyl-methyl)-8-dimethylamino-8-
phenyl-1,3-diazaspiro[4.5]decan-2-one SC_4050
CIS-1-(Cyclopropyl-methyl)-8-
dimethylamino-8-phenyl-3-[1-(pyridine-4-
carbonyl)-piperidin-4-yl]-1,3-diazaspiro[4.5]decan-2-one SC_4051
CIS-1-(Cyclopropyl-methyl)-8-dimethylamino-
3-[(4-hydroxy-tetrahydro-pyran-4-
yl)-methyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one SC_4052
CIS-1-(Cyclobutyl-methyl)-8-dimethylamino-
3-[2-(4-hydroxy-tetrahydro-pyran-4-
yl)-ethyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one SC_4053
CIS-3-[(1-Acetyl-piperidin-4-yl)-methyl]-
1-(cyclopropyl-methyl)-8-dimethylamino-
8-phenyl-1,3-diazaspiro[4.5]decan-2-one SC_4054
CIS-1-(Cyclopropyl-methyl)-8-dimethylamino-
8-phenyl-3-piperidin-4-yl-1,3- diazaspiro[4.5]decan-2-one SC_4055
CIS-1-(Cyclopropyl-methyl)-8-dimethylamino-
3-(2-hydroxy-2-methyl-propyl)-8-
phenyl-1,3-diazaspiro[4.5]decan-2-one SC_4056
CIS-1-(Cyclopropyl-methyl)-8-dimethylamino-
8-phenyl-3-(1-pyrimidin-5-yl-
piperidin-4-yl)-1,3-diazaspiro[4.5]decan-2-one SC_4057
CIS-1-(Cyclopropyl-methyl)-8-dimethylamino-
8-phenyl-3-(1-phenyl-piperidin-4-
yl)-1,3-diazaspiro[4.5]decan-2-one SC_4058
CIS-1-(Cyclopropyl-methyl)-8-dimethylamino-
8-phenyl-3-(piperidin-4-yl-methyl)- 1,3-diazaspiro[4.5]decan-2-one
SC_4059 CIS-3-(1-Benzoyl-piperidin-4-yl)-8-dimethylamino-
8-phenyl-1,3-diazaspiro[4.5]decan-2-one SC_4060
CIS-8-Dimethylamino-8-phenyl-3-[1-
(pyridine-4-carbonyl)-piperidin-4-yl]-1,3-
diazaspiro[4.5]decan-2-one SC_4061
CIS-3-(1-Acetyl-piperidin-4-yl)-8-dimethylamino-
8-phenyl-1,3-diazaspiro[4.5]decan-2-one SC_4062
CIS-1-(Cyclopropyl-methyl)-8-dimethylamino-
3-[(4-hydroxy-1,1-dioxo-thian-4-
yl)-methyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one SC_4063
CIS-8-Dimethylamino-1-[(1-hydroxy-
cyclobutyl)-methyl]-3-(2-hydroxy-2-methyl-
propyl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one SC_4064
CIS-3-[(1-Amino-cyclopropyl)-methyl]-1-
(cyclopropyl-methyl)-8-dimethylamino-
8-phenyl-1,3-diazaspiro[4.5]decan-2-one SC_4066
CIS-8-Dimethylamino-1,3-bis(2- methylsulfonyl-ethyl)-8-phenyl-1,3-
diazaspiro[4.5]decan-2-one SC_4067
CIS-N-[1-[[1-(Cyclopropyl-methyl)-8-
dimethylamino-2-oxo-8-phenyl-1,3-
diazaspiro[4.5]decan-3-yl]-methyl]-cyclopropyl]-acetamide SC_4068
CIS-1-(Cyclopropyl-methyl)-8-dimethylamino-
8-phenyl-3-[(1-pyrimidin-5-yl-
piperidin-4-yl)-methyl]-1,3-diazaspiro[4.5]decan-2-one SC_4069
CIS-8-Dimethylamino-8-phenyl-3-[(1-
pyrimidin-5-yl-piperidin-4-yl)-methyl]-1,3-
diazaspiro[4.5]decan-2-one SC_4070
CIS-8-Dimethylamino-8-phenyl-3-(1-
pyrimidin-5-yl-piperidin-4-yl)-1,3- diazaspiro[4.5]decan-2-one
SC_4071 CIS-1-(Cyclobutyl-methyl)-8-dimethylamino-
3-[2-(3-hydroxy-oxetan-3-yl)-ethyl]-
8-phenyl-1,3-diazaspiro[4.5]decan-2-one SC_4072
CIS-1-(Cyclopropyl-methyl)-8-dimethylamino-
3-[2-methyl-2-(2-oxo-pyrrolidin-1-
yl)-propyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one SC_4073
CIS-1-(Cyclopropyl-methyl)-8-dimethylamino-
3-[2-(1,1-dioxo-[1,2]thiazolidin-2-yl)-2-methyl-
propyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one SC_4074
CIS-8-Dimethylamino-1-[(1-hydroxy-
cyclobutyl)-methyl]-3-[2-(4-hydroxy-
tetrahydro-pyran-4-yl)-ethyl]-8-phenyl-
1,3-diazaspiro[4.5]decan-2-one SC_4075
CIS-1-(Cyclobutyl-methyl)-8-dimethylamino-
3-[2-(4-hydroxy-1,1-dioxo-thian-4-
yl)-ethyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one SC_4076
CIS-3-[(1-Acetyl-piperidin-4-yl)-methyl]-
8-dimethylamino-8-phenyl-1,3- diazaspiro[4.5]decan-2-one SC_4077
CIS-8-Dimethylamino-3-(2-methylsulfonyl-
ethyl)-1-(2-oxo-2-pyrrolidin-1-yl-
ethyl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one SC_4078
TRANS-8-Dimethylamino-3-(2-methylsulfonyl-
ethyl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one SC_4079
CIS-8-Dimethylamino-1-[(1-hydroxy-
cyclobutyl)-methyl]-3-[2-(4-hydroxy-1,1-
dioxo-thian-4-yl)-ethyl]-8-phenyl- 1,3-diazaspiro[4.5]decan-2-one
SC_4080 CIS-8-Dimethylamino-8-phenyl-3-(1-phenyl-
piperidin-4-yl)-1,3-diazaspiro[4.5]decan-2-one SC_4081
CIS-N-[2-[1-(Cyclopropyl-methyl)-
8-dimethylamino-2-oxo-8-phenyl-1,3-
diazaspiro[4.5]decan-3-yl]-1,1-dimethyl-ethyl]-acetamide SC_4082
CIS-N-[2-[1-(Cyclopropyl-methyl)-
8-dimethylamino-2-oxo-8-phenyl-1,3-
diazaspiro[4.5]decan-3-yl]-1,1-dimethyl- ethyl]-methanesulfonic
acid amide SC_4083 CIS-8-Dimethylamino-1-[(1-hydroxy-
cyclobutyl)-methyl]-3-[2-(3-hydroxy-oxetan-
3-yl)-ethyl]-8-phenyl-1,3- diazaspiro[4.5]decan-2-one SC_4084
CIS-1-[2-[1-(Cyclopropyl-methyl)-8-
dimethylamino-2-oxo-8-phenyl-1,3- diazaspiro[4.5]decan-3-yl]-1,1-
dimethyl-ethyl]-pyrrolidine-2,5-dione SC_4085
CIS-N-[2-[8-Dimethylamino-1-[(1-
hydroxy-cyclobutyl)-methyl]-2-oxo-8-phenyl-1,3-
diazaspiro[4.5]decan-3-yl]-1,1-dimethyl-ethyl]-acetamide SC_4086
CIS-N-[2-[8-Dimethylamino-1-[(1-hydroxy-
cyclobutyl)-methyl]-2-oxo-8-phenyl-
1,3-diazaspiro[4.5]decan-3-yl]-1,1-dimethyl- ethyl]-methanesulfonic
acid amide SC_4087 CIS-1-(Cyclopropyl-methyl)-8-
dimethylamino-8-phenyl-3-(1-pyridin-3-yl-
pipendin-4-yl)-1,3-diazaspiro[4.5]decan-2-one SC_4088
CIS-1-(Cyclopropyl-methyl)-8-
dimethylamino-8-(3-fluorophenyl)-3-(2-
methylsulfonyl-ethyl)-1,3-diazaspiro[4.5]decan-2-one SC_4089
CIS-1-(Cyclopropyl-methyl)-8-
dimethylamino-8-phenyl-3-(1-pyridin-4-yl-
pipendin-4-yl)-1,3-diazaspiro[4.5]decan-2-one
SC_4090 CIS-8-Dimethylamino-1-[(1-hydroxy-
cyclobutyl)-methyl]-3-[2-methyl-2-(2-oxo-pyrrolidin-1-
yl)-propyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one SC_4091
CIS-1-(Cyclobutyl-methyl)-8-dimethylamino-
3-(2-methyl-2-methylsulfonyl-
propyl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one SC_4092
TRANS-1-(Cyclobutyl-methyl)-8-
dimethylamino-3-(2-methyl-2-methylsulfonyl-
propyl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one SC_4093
CIS-8-Dimethylamino-3-[2-(1,1-dioxo-
[1,2]thiazolidin-2-yl)-2-methyl-propyl]-1-
[(1-hydroxy-cyclobutyl)-methyl]-8-phenyl-
1,3-diazaspiro[4.5]decan-2-one SC_4094
CIS-1-(Cyclopropyl-methyl)-8-dimethylamino-
8-(3-fluorophenyl)-3-[(4-hydroxy-
tetrahydro-pyran-4-yl)-methyl]-1,3- diazaspiro[4.5]decan-2-one
SC_4095 CIS-8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-
methyl]-8-phenyl-3-(1-pyrimidin-5-yl-piperidin-
4-yl)-1,3-diazaspiro[4.5]decan-2-one SC_4096
CIS-1-(Cyclopropyl-methyl)-8-dimethylamino-
8-phenyl-3-(1-pyridazin-4-yl-
piperidin-4-yl)-1,3-diazaspiro[4.5]decan-2-one SC_4097
CIS-2-[8-Dimethylamino-3-(2-methylsulfonyl-
ethyl)-2-oxo-8-phenyl-1,3-
diazaspiro[4.5]decan-1-yl]-N,N-dimethyl-acetamide SC_4098
TRANS-8-Dimethylamino-1-[(1-
hydroxy-cyclobutyl)-methyl]-3-(2-methylsulfonyl-
ethyl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one SC_4099
CIS-1-(Cyclopropyl-methyl)-8-dimethylamino-
8-(3-fluorophenyl)-3-(1-pyrimidin-
5-yl-piperidin-4-yl)-1,3-diazaspiro[4.5]decan-2-one SC_4100
CIS-1-(cyclopropylmethyl)-8-(3- fluorophenyl)-8-(methylamino)-3-(2-
(methylsulfonyl)ethyl)-1,3-diazaspiro[4.5]decan-2-one SC_4101
CIS-1-(cyclopropylmethyl)-8-(dimethylamino)-
3-((1-hydroxycyclobutyl)methyl)-
8-phenyl-1,3-diazaspiro[4.5]decan-2-one SC_4102
CIS-8-(dimethylamino)-8-(3-fluorophenyl)-
3-((4-hydroxy-1,1-dioxidotetrahydro-2H-thiopyran-
4-yl)methyl)-1-((1-hydroxycyclobutypmethyl)-1,3-
diazaspiro[4.5]decan-2-one SC_4103
CIS-8-(dimethylamino)-8-(3-fluorophenyl)-
1-((1-hydroxycyclobutyl)methyl)-3-
((4-hydroxytetrahydro-2H-pyran-4-yl)methyl)-
1,3-diazaspiro[4.5]decan-2-one SC_4104
CIS-1-(cyclopropylmethyl)-8-(dimethylamino)-
8-(3-fluorophenyl)-3-((4-hydroxy-
1,1-dioxidotetrahydro-2H-thiopyran-4-yl)methyl)-
1,3-diazaspiro[4.5]decan-2-one SC_4105
CIS-1-(cyclopropylmethyl)-8-(dimethylamino)-
3-(oxetan-3-ylmethyl)-8-phenyl- 1,3-diazaspiro[4.5]decan-2-one
SC_4106 CIS-8-(dimethylamino)-8-phenyl-3-((S)-1-
(thiophen-3-yl)propan-2-yl)-1,3- diazaspiro[4.5]decan-2-one SC_4107
CIS-8-(dimethylamino)-8-phenyl-1,3-bis((1-
(trifluoromethyl)cyclopropyl)methyl)-
1,3-diazaspiro[4.5]decan-2-one SC_4108
CIS-8-(dimethylamino)-1,3-bis((1-
fluorocyclopropyl)methyl)-8-phenyl-1,3- diazaspiro[4.5]decan-2-one
SC_4109 CIS-1-(cyclopropylmethyl)-8-(dimethylamino)-
3-((3-(hydroxymethyl)oxetan-3-
yl)methyl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one SC_4110
CIS-3-((3-aminooxetan-3-yl)methyl)-1-
(cyclopropylmethyl)-8-(dimethylamino)-8-
phenyl-1,3-diazaspiro[4.5]decan-2-one SC_4111
CIS-1-((1-(cyclopropylmethyl)-8-
(dimethylamino)-2-oxo-8-phenyl-1,3-
diazaspiro[4.5]decan-3-yl)methyl)cyclobutanecarbonitrile SC_4112
CIS-3-(8-(dimethylamino)-1-((1-
fluorocyclopropyl)methyl)-2-oxo-8-phenyl-1,3-
diazaspiro[4.5]decan-3-yl)-2,2-dimethylpropanenitrile SC_5061
CIS-3-[8-(Ethyl-methyl-amino)-2-oxo-8-
phenyl-1,3-diazaspiro[4.5]decan-3-yl]- 2,2-dimethyl-propionitrile
SC_5062 CIS-3-(8-Dimethylamino-2-oxo-8-phenyl-
1,3-diazaspiro[4.5]decan-3-yl)-2,2- dimethyl-propionitrile SC_5063
CIS-2,2-Dimethyl-3-(8-methylamino-2-oxo-8-
phenyl-1,3-diazaspiro[4.5]decan-3- yl)-propionitrile SC_5065
CIS-3-[8-(Ethyl-methyl-amino)- 1-methyl-2-oxo-8-phenyl-1,3-
diazaspiro[4.5]decan-3-yl]-2,2-dimethyl-propionitrile SC_5068
CIS-3-(8-Ethylamino-2-oxo-8-phenyl-1,3-
diazaspiro[4.5]decan-3-yl)-2,2-dimethyl- propionitrile SC_5075
CIS-3-[1-(Cyclopropyl-methyl)-8- dimethylamino-2-oxo-8-phenyl-1,3-
diazaspiro[4.5]decan-3-yl]-2,2-dimethyl-propionitrile SC_5080
TRANS-3-[1-(Cyclopropyl-methyl)-
8-dimethylamino-2-oxo-8-phenyl-1,3-
diazaspiro[4.5]decan-3-yl]-2,2-dimethyl-propionitrile
and the physiologically acceptable salts thereof.
[0056] 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.
[0057] 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.
[0058] 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--.
[0059] 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)--.
[0060] 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.
[0061] 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 deca-hydroquinoxalin, 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.
[0062] 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.
[0063] 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.
[0064] 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.
[0065] 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.
[0066] 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.
[0067] 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.
[0068] 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.
[0069] 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.
[0070] 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.
[0071] 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.
[0072] 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.
[0073] Preferably, the compounds according to the invention have a
structure according to general formula (I')
##STR00009##
wherein R.sup.1 to R.sup.5, R.sup.10 to R.sup.20 are defined as
above, or a physiologically acceptable salt thereof.
[0074] 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.
[0075] Preferably, the compounds according to the invention have a
structure according to general formula (IX)
##STR00010##
wherein R.sup.C means --H or --OH; R.sup.3 means -phenyl or
-3-fluorophenyl; R.sup.5 means C.sub.1-C.sub.6-alkyl, linear or
branched, saturated, unsubstituted or monosubstituted with --OH,
--CN, --NH.sub.2, --NHC(.dbd.O)C.sub.1-C.sub.4-alkyl,
--NHS(.dbd.O).sub.2--C.sub.1-C.sub.4-alkyl, or
--S(.dbd.O).sub.2--C.sub.1-C.sub.4-alkyl; or 3-6-membered
heterocycloalkyl, saturated, unsubstituted or substituted with
--OH; wherein said 3-6-membered heterocycloalkyl is optionally
connected through --CH.sub.2-- or --(CH.sub.2).sub.2--; or a
physiologically acceptable salt thereof.
[0076] Preferably, the 3-6-membered heterocycloalkyl is selected
from the group consisting of oxetanly, tetrahydrofuranyl and
tetrahydropyranyl.
[0077] In a preferred embodiment, the compounds according to the
invention are in the form of the free bases.
[0078] In another preferred embodiment, the compounds according to
the invention are in the form of the physiologically acceptable
salts.
[0079] 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.
[0080] 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.
[0081] 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.
[0082] 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.
[0083] 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".
[0084] 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.
[0085] The compounds according to the invention potently bind to
the MOP and/or KOP and/or DOP and/or NOP receptors.
[0086] 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.
[0087] 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.
[0088] 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.
[0089] 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.
[0090] 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.
[0091] 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.
[0092] 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.
[0093] 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
[0094] have agonist activity at the NOP receptor, but no
significant activity at the MOP receptor; [0095] have agonist
activity at the NOP receptor, but no significant activity at the
KOP receptor; [0096] have agonist activity at the NOP receptor, but
no significant activity at the DOP receptor; [0097] 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; [0098] 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 [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 as well as
no significant activity at the DOP receptor.
[0100] 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 [0101] have agonist activity
at the NOP receptor as well as agonist activity at the MOP
receptor; [0102] 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; [0103] 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; [0104] 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; [0105] have agonist activity at the NOP receptor as well
as agonist activity at the MOP receptor, but no significant
activity at the KOP receptor; [0106] 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 [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 as well
as no significant activity at the DOP receptor.
[0108] 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 [0109] have agonist activity
at the NOP receptor as well as agonist activity at the KOP
receptor; [0110] 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; [0111] 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; [0112] have agonist activity
at the NOP receptor as well as agonist activity at the KOP
receptor, but no significant activity at the MOP receptor; [0113]
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 [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 as well as no significant activity at
the DOP receptor.
[0115] 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 [0116] have agonist activity
at the NOP receptor as well as agonist activity at the DOP
receptor; [0117] have agonist activity at the NOP receptor as well
as agonist activity at the DOP receptor, but no significant
activity at the MOP receptor; [0118] 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 [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 as well
as no significant activity at the KOP receptor.
[0120] 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
[0121] have agonist activity at the KOP receptor, but no
significant activity at the MOP receptor; [0122] have agonist
activity at the KOP receptor, but no significant activity at the
NOP receptor; [0123] have agonist activity at the KOP receptor, but
no significant activity at the DOP receptor; [0124] 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; [0125] 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 [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 as well as
no significant activity at the DOP receptor.
[0127] 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 [0128] 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; [0129] 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; [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 as well as
antagonist activity at the NOP receptor; or [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, no
significant activity at the NOP receptor.
[0132] 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
[0133] have agonist activity at the NOP receptor, but no
significant activity at the MOP receptor; [0134] have agonist
activity at the NOP receptor, but no significant activity at the
KOP receptor; [0135] have agonist activity at the NOP receptor, but
no significant activity at the DOP receptor; [0136] 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; [0137] 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 [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 as well as
no significant activity at the DOP receptor.
[0139] 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
[0140] have antagonist activity at the NOP receptor, but no
significant activity at the MOP receptor; [0141] have antagonist
activity at the NOP receptor, but no significant activity at the
KOP receptor; [0142] have antagonist activity at the NOP receptor,
but no significant activity at the DOP receptor; [0143] 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; [0144] 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 [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 as well as no significant activity at the DOP
receptor.
[0146] 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 [0147] have antagonist
activity at the NOP receptor as well as agonist activity at the DOP
receptor; [0148] have antagonist activity at the NOP receptor as
well as agonist activity at the DOP receptor, but no significant
activity at the MOP receptor; [0149] 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 [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 as well as no significant activity at the KOP
receptor.
[0151] 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.
[0152] A further aspect of the invention relates to the compounds
according to the invention as medicaments.
[0153] 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.
[0154] 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.
[0155] 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.
[0156] 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.
[0157] The pharmaceutical composition according to the invention
can optionally contain suitable additives and/or auxiliary
substances and/or optionally further active ingredients.
[0158] 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).
[0159] 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.
[0160] The pharmaceutical composition according to the invention is
preferably for systemic, topical or local administration,
preferably for oral administration.
[0161] Another aspect of the invention relates to a pharmaceutical
dosage form which contains the pharmaceutical composition according
to the invention.
[0162] 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.
[0163] 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.
[0164] 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.
[0165] 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.
[0166] 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.
[0167] Preferred synthesis routes are described below:
[0168] 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.
[0169] 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):
##STR00011##
wherein R.sup.1, R.sup.2 and R.sup.3 are defined as above.
[0170] 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):
##STR00012##
wherein R.sup.1, R.sup.2 and R.sup.3 are defined as above and PG is
a protecting group.
[0171] 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):
##STR00013##
wherein R.sup.1, R.sup.2 and R.sup.3 are defined as above.
[0172] 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.
[0173] In yet another preferred embodiment, the synthesis of the
compounds according to the invention proceeds via a synthesis route
which comprises the preparation of [0174] an intermediate according
to general formula (IIIa) and according to general formula (IIIb);
or [0175] an intermediate according to general formula (IIIa) and
according to general formula (IIIc); or [0176] an intermediate
according to general formula (IIIb) and according to general
formula (IIIc); or [0177] an intermediate according to general
formula (IIIa), according to general formula (IIIb) and according
to general formula (IIIc).
[0178] The following examples further illustrate the invention but
are not to be construed as limiting its scope.
EXAMPLES
[0179] "RT" means room temperature (23.+-.7.degree. C.), "M" are
indications of concentration in mol/l, "aq." means aqueous, "sat."
means saturated, "sol." means solution, "conc." means
concentrated.
[0180] Further abbreviations:
brine saturated aqueous sodium chloride solution CC column
chromatography cHex cyclohexane DCM dichloromethane
DIPEA N,N-diisopropylethylamine
DMF N,N-dimethylformamide
Et Ethyl
[0181] 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
[0182] m/z mass-to-charge ratio MeOH methanol MeCN acetonitrile min
minutes MS mass spectrometry NBS N-bromo-succinimide NEt.sub.3
triethylamine
PE Petrol Ether (60-80.degree. C.)
[0183] 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
[0184] The yields of the compounds prepared were not optimised. All
temperatures are uncorrected.
[0185] 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, respectively, for example) or can be prepared using the
conventional methods known to the person skilled in the art.
[0186] The mixing ratios of solvents or eluents for chromatography
are specified in v/v.
[0187] All the intermediate products and exemplary compounds were
analytically characterised by mass spectrometry (MS, m/z for
[M+H].sup.+). In addition .sup.1H-NMR and .sup.13C spectroscopy was
carried out for all the exemplary compounds and selected
intermediate products.
[0188] Remark Regarding Stereochemistry
[0189] 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:
##STR00014##
[0190] 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:
##STR00015##
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
##STR00016##
[0191] 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
[0192] 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
[0193] 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-951:
CIS-1-[(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-1-yl)-met-
hyl]-cyclobutane-1-carbonitrile
##STR00017##
[0194] Step 1:
1-((CIS-8-(dimethylamino)-3-(4-methoxybenzyl)-2-oxo-8-phenyl-1,3-diazaspi-
ro[4.5]decan-1-yl)methyl)cyclobutanecarbonitrile
[0195] 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 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
[0196] 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
[0197] 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
##STR00018##
[0199] 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
##STR00019##
[0200] Step 1:
1-Cyclobutylmethyl-3-(4-methoxy-benzyl)-9,12-dioxa-1,3-diaza-dispiro[4.2.-
4.2]tetradecan-2-one
[0201] 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
[0202] 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).fwdarw.(3:7)) to give
1-cyclobutylmethyl-3-(4-methoxy-benzyl)-1,3-diaza-spiro[4.5]decane-2,8-di-
one (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
[0203] 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=0.45. The product was
used for the next step without additional purification.
Step 4:
CIS-1-(cyclobutylmethyl)-8-(isobutyl(methyl)amino)-3-(4-methoxyben-
zyl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one
[0204] 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, -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-methoxybe-
nzyl)-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
[0205] 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
##STR00020##
[0206] Step 1: Ethyl
5-cyano-2-oxo-5-(pyridin-2-yl)cyclohexanecarboxylate
[0207] 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; Rf:
0.65).
Step 2: 4-Oxo-1-pyridin-2-yl-cyclohexane-1-carbonitrile
[0208] 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; Rf: 0.45). [M+H].sup.+ 201.1
Synthesis of INT-961:
4-Dimethylamino-4-pyridin-2-yl-cyclohexan-1-one
##STR00021##
[0209] Step 1:
8-(pyridin-2-yl)-1,4-dioxaspiro[4.5]decane-8-carbonitrile
[0210] 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% ethyl acetate in petroleum
ether; Rf: 0.55).
Step 2:
8-(pyridin-2-yl)-1,4-dioxaspiro[4.5]decane-8-carboxamide
[0211] 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
[0212] 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
[0213] 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
[0214] 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
##STR00022##
[0215] Step 1: 8-(Dimethylamino)-1,4-dioxaspiro
4.5]decane-8-carbonitrile
[0216] 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
[0217] 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
[0218] 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
##STR00023##
[0219] Step 1: 9,12-Dioxa-2,4-diazadispiro[4.2.4 {8}0.2
{5}]tetradecane-1,3-dione
[0220] 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
[0221] 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
{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}0.2 {5}]tetradecan-3-one
[0222] 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
[0223] 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
##STR00024##
[0224] Step 1:
CIS-8-(dimethylamino)-1-isobutyl-3-(4-methoxybenzyl)-8-phenyl-1,3-diazasp-
iro[4.5]decan-2-one
[0225] 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
[0226] 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
##STR00025##
[0227] Step 1:
8-(dimethylamino)-3-(4-methoxybenzyl)-2-oxo-1,3-diazaspiro[4.5]decane-8-c-
arbonitrile
[0228] 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-methoxyphenyl)-methyl-
]-1,3-diazaspiro[4.5]decan-2-one
[0229] 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
##STR00026##
[0231] 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
##STR00027##
[0232] Step 1:
8-(dimethylamino)-8-phenyl-1,3-diazaspiro[4,5]decane-2,4-dione
[0233] 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
[0234] 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
[0235] 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
##STR00028##
[0236] 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
[0237] 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
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
[0238]
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
##STR00029##
[0240]
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
##STR00030##
[0241] Step 1:
CIS-8-(dimethylamino)-3-(4-methoxybenzyl)-1-((1-methylcyclobutyl)methyl)--
8-phenyl-1,3-diazaspiro[4.5]decan-2-one
[0242] 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-(Bromo-methyl)-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
[0243] 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
##STR00031##
[0244] Step 1:
CIS-8-(dimethylamino)-1-isobutyl-3-(4-methoxybenzyl)-8-phenyl-1,3-diazasp-
iro[4.5]decan-2-one
[0245] 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)-1-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
[0246] 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
##STR00032##
[0247] Step 1:
CIS-3-benzyl-1-(cyclobutylmethyl)-8-(methylamino)-8-phenyl-1,3-diazaspiro-
[4.5]decan-2-one
[0248] 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
[0249] 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)
[0250] Sodium metal (1.18 g, 51.68 mmol, 10 equiv.) was added to
liquid ammonia (.about.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
##STR00033##
[0252] 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-988:
CIS-8-(dimethylamino)-1-(2-(1-methoxycyclobutyl)ethyl)-8-phenyl-1,3-diaza-
spiro[4.5]decan-2-one
##STR00034##
[0253] Step 1:
CIS-8-(dimethylamino)-1-[2-(1-methoxycyclobutyl)ethyl]-3-[(4-methoxypheny-
l)methyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one
[0254] Sodium hydroxide (78.06 mg, 4.0 equiv.) was suspended in
DMSO (3.5 mL), stirred for 10 minutes,
8-(dimethylamino)-3-[(4-methoxyphenyl)methyl]-8-phenyl-1,3-diazaspiro[4.5-
]decan-2-one (INT-975) (192.0 mg, 1.0 equiv.) was added, the
reaction mixture was stirred for 5 min followed by addition of
2-(1-methoxycyclobutyl)ethyl 4-methylbenzenesulfonate (416.2 mg,
3.0 equiv.) in DMSO (1.5 mL). The resulting mixture was stirred
overnight at 50.degree. C. The reaction mixture was quenched with
water and extracted with DCM (3.times.20 mL). The combined organic
phases were washed with brine, dried over Na.sub.2SO.sub.4 and
concentrated under reduced pressure. The residue (283 mg yellow
oil) was purified by column chromatography on silica gel (eluent
DCM/EtOH 98/2 to 96/4) to give
8-(dimethylamino)-1-[2-(1-methoxycyclobutyl)ethyl]-3-[(4-methoxyphenyl)me-
thyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one 163 mg (66%).
Step 2:
CIS-8-(dimethylamino)-1-(2-(1-methoxycyclobutyl)ethyl)-8-phenyl-1,-
3-diazaspiro[4.5]decan-2-one (INT-988)
[0255] In analogy to the method described for INT-982 step 2
CIS-8-(dimethylamino)-1-[2-(1-methoxycyclobutyl)ethyl]-3-[(4-methoxypheny-
l)methyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one was converted
into
CIS-8-(dimethylamino)-1-(2-(1-methoxycyclobutyl)ethyl)-8-phenyl-1,3-diaza-
spiro[4.5]decan-2-one (INT-988). Mass: m/z 386.3 (M+H).sup.+.
Synthesis of INT-1008:
CIS-8-ethylamino-8-phenyl-1,3-diaza-spiro[4.5]decan-2-one
##STR00035##
[0256] Step 1 and step 2:
ethyl-(8-phenyl-1,4-dioxa-spiro[4.5]dec-8-yl)-amine hydrochloride
(INT-1004)
[0257] 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 and the
residue was diluted with ether (60 ml), and a freshly prepared PhLi
solution was added [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). The reaction mixture was stirred at
RT for 1.5 h, quenched with saturated NH.sub.4Cl solution (100 ml)
at 0.degree. C. and extracted with ethyl acetate (2.times.750 ml).
The combined organic layer was washed with water (3.times.350 ml),
brine (300 ml), dried over Na.sub.2SO.sub.4 and concentrated under
reduced pressure. The resulting residue was dissolved in ethyl
methyl ketone (100 ml) and trimethylsilyl chloride (37.5 ml) was
added at 0.degree. C. The resulting mixture was stirred at RT for
16 h. The precipitated solid was filtered off and washed with
acetone followed by THF to get
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).sup.+.
Step 3: 4-ethylamino-4-phenyl-cyclohexanone (INT-1005)
[0258] 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. aq.
HCl (62.5 ml) at 0.degree. C. and the resulting mixture was stirred
at RT for 16 h. The reaction mixture was basified with aq. NaOH (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 the yield is given for 2
combined batches. Yield: 92% (17.0 g, 78.34 mmol).
Step 4: cis and trans mixture of
8-ethylamino-8-phenyl-1,3-diaza-spiro[4.5]decane-2,4-dione
(INT-1006 and INT-1007)
[0259] 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 added and stirring was continued at 60.degree.
C. for 18 h. The reaction mixture was cooled down to RT. The
precipitated solid 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 of
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)
[0260] 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, 960 ml) was added a solution of L-tartaric acid
in MeOH (25 ml) and the resulting mixture stirred at RT for 2 h and
then kept in refrigerator for 16 h. The precipitated solid was
filtered off and washed with MeOH-DCM (1:5, 50 ml) to get tartrate
salt of 8-ethylamino-8-phenyl-1,3-diaza-spiro[4.5]decane-2,4-dione
(7.5 g) as a white solid. To this solid sat. aq. NaHCO.sub.3 was
added (pH-8) and the resulting mixture was extracted with 25%
MeOH-DCM (2.times.800 ml). Combined organic layer was washed with
water (300 ml), brine (300 ml), dried over anhydrous
Na.sub.2SO.sub.4 and concentrated under reduced pressure. The
residue was triturated with 20% DCM-hexane and the resulting solid
was dried under reduced pressure to afford
CIS-8-ethylamino-8-phenyl-1,3-diaza-spiro[4.5]decane-2,4-dione as
white solid. This step was done in 2 batches (12 g & 2.4 g) and
the 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)
[0261] To a slurry of LiAlH.sub.4 (793 mg, 20.91 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, 6.97 mmol, 1.0 eq.) in THF (60 ml) at 0.degree. C. and the
reaction mixture was heated to 65.degree. C. for 16 h. The reaction
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 pad. The residue 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 to give
crude product which 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+1].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
##STR00036##
[0262] Step 1:
2-methyl-N-(1,4-dioxaspiro[4.5]decan-8-ylidene)propane-2-sulfinamide
[0263] 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
[0264] 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
[0265] 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
[0266] 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)
[0267] 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
[0268] 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
[0269]
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)methyl)amino)-8-phenyl-1,3-dia-
zaspiro[4.5]decane-2,4-dione
[0270] 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-C.sub.18 (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)
[0271] 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, Rf: 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
##STR00037##
[0272] Step 1:
CIS-1-(Cyclobutyl-methyl)-8-dimethylamino-8-(3-fluorophenyl)-3-[(4-methox-
yphenyl)-methyl]-1,3-diazaspiro[4.5]decan-2-one
[0273] 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
[0274] 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
##STR00038##
[0275] Step 1: 9,12-dioxa-2,4-diazadispiro[4.2.4 {8}0.2
{5}]tetradecan-3-one
[0276] Lithiumaluminiumhydride (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
[0277] 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)
[0278] 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
##STR00039##
[0280] 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).sup.+.
Synthesis of INT-1052:
CIS-3-(2-amino-2-methylpropyl)-1-(cyclopropylmethyl)-8-(dimethylamino)-8--
phenyl-1,3-diazaspiro[4.5]decan-2-one
##STR00040##
[0281] Step 1:
CIS-3-(1-(cyclopropylmethyl)-8-(dimethylamino)-2-oxo-8-phenyl-1,3-diazasp-
iro[4.5]decan-3-yl)-2,2-dimethylpropanenitrile
[0282] NaH (60% in mineral oil) (1.76 g, 44.04 mmol) was added to
the solution of
CIS-1-(cyclopropylmethyl)-8-(dimethylamino)-8-phenyl-1,3-diazaspiro[4.5]d-
ecan-2-one (INT-983) (3.6 g, 11.01 mmol) in DMSO (150 mL) at RT
under argon atmosphere. 2-Cyano-2-methylpropyl
4-methylbenzenesulfonate (113 mg, 0.45 mmol) was added to the
reaction mixture in one portion. The reaction mixture was heated at
70.degree. C. for 16 h. The reaction mixture was cooled to
0.degree. C. and quenched with water (20 mL). The organic product
was extracted with EtOAc (2.times.200 mL). The combined organic
extracts were dried over anhydr. Na.sub.2SO.sub.4 and concentrated
under reduced pressure. The resulting crude product was purified by
column chromatography (silica gel 100-200 mesh, 0-10% MeOH in DCM)
to get 2.1 g, 46% of
CIS-3-(1-(cyclopropylmethyl)-8-(dimethylamino)-2-oxo-8-phenyl-1,3-diazasp-
iro[4.5]decan-3-yl)-2,2-dimethylpropanenitrile as an off-white
solid (TLC system: 5% MeOH in DCM; Rf: 0.60).
Step 2:
CIS-3-(1-(cyclopropylmethyl)-8-(dimethylamino)-2-oxo-8-phenyl-1,3--
diazaspiro[4.5]decan-3-yl)-2,2-dimethylpropanamide
[0283] H.sub.2O.sub.2 (30% in water) (8 mL) was added to a solution
of
CIS-3-(1-(cyclopropylmethyl)-8-(dimethylamino)-2-oxo-8-phenyl-1,3-diazasp-
iro[4.5]decan-3-yl)-2,2-dimethylpropanenitrile (2.0 g, 4.90 mmol)
in DMSO (50 mL) at RT under argon atmosphere. A solution of KOH
(1.1 g, 19.6 mmol) in water (10 mL) was added dropwise to the
reaction mixture. The reaction mixture was stirred at RT for 16 h.
The reaction mixture was diluted with water (300 mL) and the
organic product was extracted with EtOAc (2.times.100 mL). The
combined organic extracts were dried over anhydrous
Na.sub.2SO.sub.4 and concentrated under reduced pressure. The
resulting crude product was purified by column chromatography
(silica gel 100-200 mesh, 0-5% MeOH in DCM) to get 0.44 g (21%) of
CIS-3-(1-(cyclopropylmethyl)-8-(dimethylamino)-2-oxo-8-phenyl-1,3-diazasp-
iro[4.5]decan-3-yl)-2,2-dimethylpropanamide as a gummy solid (TLC
system: 5% MeOH in DCM; Rf: 0.30) and 1.1 g of
CIS-3-(1-(cyclopropylmethyl)-8-(dimethylamino)-2-oxo-8-phenyl-1,3-diazasp-
iro[4.5]decan-3-yl)-2,2-dimethylpropanenitrile was also reisolated
(TLC system: 5% MeOH in DCM; Rf: 0.30).
Step 3:
CIS-3-(2-amino-2-methylpropyl)-1-(cyclopropylmethyl)-8-(dimethylam-
ino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one (INT-1052)
[0284] PhI(OCOCF.sub.3).sub.2 (703.5 mg, 1.636 mmol) was added to a
solution of
CIS-3-(1-(cyclopropylmethyl)-8-(dimethylamino)-2-oxo-8-phenyl-1,3-diazasp-
iro[4.5]decan-3-yl)-2,2-dimethylpropanamide (410 mg, 0.962 mmol) in
mixture of acetonitrile (15 mL) and water (15 mL) at RT under argon
atmosphere. The reaction mixture was stirred for 18 h at RT. The
reaction mixture was diluted with water (15 mL) and the aqueous
layer was washed with EtOAc (2.times.20 mL). The water layer was
basified with solid NaHCO.sub.3 and the organic product was
extracted with EtOAc (2.times.30 mL). The organic layer was dried
over anhydr. Na.sub.2SO.sub.4 and solvent was concentrated under
reduced pressure to afford 350 mg, 91% of
CIS-3-(2-amino-2-methylpropyl)-1-(cyclopropylmethyl)-8-(dimethylamino)-8--
phenyl-1,3-diazaspiro[4.5]decan-2-one as gummy solid (TLC system:
5% MeOH in DCM; Rf: 0.15). Mass: m/z 399.3 (M+H).sup.+.
Synthesis of INT-1054:
CIS-8-(dimethylamino)-8-(m-tolyl)-1,3-diazaspiro[4.5]decan-2-one
##STR00041##
[0286] To a stirred solution of
4-dimethylamino-4-phenyl-cyclohexanone (50 g, 230.1 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 stirred for 15 min. NaCN (22.5 g,
460.83 mmol) was added to the reaction mixture and stirred for 16 h
at RT. The reaction mixture was extracted with DCM (3.times.750
ml). Organic layer was washed with water (750 ml), brine (750 ml)
and dried over Na.sub.2SO.sub.4. The solvent was evaporated under
reduced pressure. The residue was triturated with DCM/hexane to get
crude 1-amino-4-dimethylamino-4-phenyl-cyclohexanecarbonitrile (50
g, 90%) as off white solid which was used in next step without
purification. Yield: 78% (44 g, 181 mmol). Mass: m/z 244.2
(M+H).sup.+.
Synthesis of INT-1055 and INT-1056: CIS- and
TRANS-3-(2-amino-2-methylpropyl)-1-(cyclopropylmethyl)-8-(dimethylamino)--
8-phenyl-1,3-diazaspiro[4.5]decan-2-one
##STR00042##
[0287] Step 1:
N-(1-cyano-4-(dimethylamino)-4-phenylcyclohexyl)cyclobutanecarboxamide
(CIS-/TRANS mixture)
[0288] To a solution of
1-amino-4-dimethylamino-4-phenyl-cyclohexanecarbonitrile (INT-1054)
(5.0 g, 20.57 mmol, 1.0 eq.) in THF (100 mL) were added
cyclobutanecarboxylic acid (2.50 g, 24.69 mmol, 1.2 eq), DIPEA
(10.5 mL, 61.71 mmol, 3.0 eq) and T3P (18.38 mL, 30.85 mmol, 1.5
eq). The reaction mixture was stirred at RT for 16 h, diluted with
water (100 mL) and extracted with EtOAc (2.times.200 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 cyclobutanecarboxylic acid
(1-cyano-4-dimethylamino-4-phenyl-cyclohexyl)-amide as a light
yellow sticky material which was used in the next step without
further purification. Mass: m/z 326.3 (M+H).sup.+.
Step 2:
1-(aminomethyl)-N.sup.1-(cyclobutylmethyl)-N.sup.4,N.sup.4-dimethy-
l-4-phenylcyclohexane-1,4-diamine (CIS/TRANS-mixture)
[0289] To suspension of LiAlH.sub.4 (2.81 g, 73.84 mmol, 6.0 eq.)
in dry THF (25 mL) was added a solution cyclobutanecarboxylic acid
(1-cyano-4-dimethylamino-4-phenyl-cyclohexyl)-amide (4.0 g, 12.3
mmol, 1.0 eq.) in dry THF (35 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 stirred at RT for 2 h. The reaction mixture
was filtered through celite and washed with THF (100 mL). Filtrate
was concentrated under reduced pressure to get crude
1-aminomethyl-N-cyclobutylmethyl-N',N'-dimethyl-4-phenyl-cyclohexane-1,4--
diamine (3.0 g) as a light yellow sticky material which was used in
the next step without further purification. Mass: m/z 316.4
(M+H).sup.+.
Step 3:
N-((1-((cyclobutylmethyl)amino)-4-(dimethylamino)-4-phenylcyclohex-
yl)methyl)-2-methyl-2-(methylthio)propanamide
(CIS/TRANS-mixture)
[0290] To a solution of crude
1-aminomethyl-N-cyclobutylmethyl-N',N'-dimethyl-4-phenyl-cyclohexane-1,4--
diamine (3.0 g, 9.23 mmol, 1.0 eq.) in THF (50 mL) were added
2-methyl-2-methylsulfanyl-propionic acid (1.23 g, 9.23 mmol, 1.0
eq), DIPEA (4.81 mL, 27.69 mmol, 3.0 eq) and T3P (8.3 mL, 13.84
mmol, 1.5 eq, 50% solution in EtOAc) at 0.degree. C. and the
resulting mixture was stirred at RT for 16 h. The reaction mixture
was diluted with DCM (300 mL), washed with water (100 mL) and brine
(100 mL), dried over Na.sub.2SO.sub.4 and concentrated under
reduced pressure to get crude
N-[1-(cyclobutylmethyl-amino)-4-dimethylamino-4-phenyl-cyclohexylmethyl]--
2-methyl-2-methylsulfanyl-propionamide as a light yellow sticky
material which was used in the next step without further
purification. Mass: m/z 432.1 (M+H).sup.+.
Step 4:
N'-(cyclobutylmethyl)-N.sup.4,N.sup.4-dimethyl-1-(((2-methyl-2-(me-
thylthio)propyl)amino)methyl)-4-phenylcyclohexane-1,4-diamine
(CIS/TRANS-mixture)
[0291] To a solution of crude
N-[1-(cyclobutylmethyl-amino)-4-dimethylamino-4-phenyl-cyclohexylmethyl]--
2-methyl-2-methylsulfanyl-propionamide (2.5 g, 5.8 mmol, 1.0 eq.)
in THF (60 mL) was added BH.sub.3.times.Me.sub.2S (2.75 ml, 29.0
mmol, 5.0 eq.). The reaction mixture was stirred at RT for 16 h,
then quenched with MeOH (10 mL) and 2N HCl (10 mL) at 0.degree. C.
and stirred at RT for 30 min. The resulting mixture was
concentrated under reduced pressure, diluted with water (50 mL),
basified with sat. aq. NaHCO.sub.3 and extracted with DCM
(2.times.250 mL). Combined organic layer was dried over
Na.sub.2SO.sub.4 and concentrated under reduced pressure to get
crude
N-cyclobutylmethyl-N',N'-dimethyl-1-[(2-methyl-2-methylsulfanyl-propylami-
no)-methyl]-4-phenyl-cyclohexane-1,4-diamine as a light yellow
sticky material which was used in the next step without further
purification. Mass: m/z 418.4 (M+H).sup.+.
Step 5: CIS- and
TRANS-3-(2-amino-2-methylpropyl)-1-(cyclopropylmethyl)-8-(dimethylamino)--
8-phenyl-1,3-diazaspiro[4.5]decan-2-one (INT-1055 and INT-1056)
[0292] To a solution of crude
N-cyclobutylmethyl-N',N'-dimethyl-1-[(2-methyl-2-methylsulfanyl-propylami-
no)-methyl]-4-phenyl-cyclohexane-1,4-diamine (2.0 g, 4.79 mmol, 1.0
eq.) in toluene (30 ml) was added KOH (1.61 g, 28.77 mmol, 6.0 eq)
in water (60 mL) at 0.degree. C. followed by addition of COCl.sub.2
(5.84 L 16.76 mmol, 3.5 eq., 20% in toluene). The reaction mixture
was stirred at RT for 16 h, then basified with sat. aq. NaHCO.sub.3
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-1-cyclobutylmethyl-8-dimethylamino-3-(2-methyl-2-methylsulfanyl-propy-
l)-8-phenyl-1,3-diaza-spiro[4.5]decan-2-one (INT-1055) as peak 2
(45 mg) and
TRANS-1-cyclobutylmethyl-8-dimethylamino-3-(2-methyl-2-methylsulfanyl-
-propyl)-8-phenyl-1,3-diaza-spiro[4.5]decan-2-one (INT-1056) as
peak 1 (300 mg). Mass: m/z 444.1 (M+H).sup.+ (trans), m/z 444.0
(M+H).sup.+ (cis).
Synthesis of INT-1059:
TRANS-8-(dimethylamino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one
##STR00043##
[0293] Step 1:
TRANS-8-(dimethylamino)-8-phenyl-1,3-diazaspiro[4.5]decane-2,4-dione
[0294] 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 -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)
[0295] 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).sup.+.
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
##STR00044##
[0296] Step 1:
1-amino-4-dimethylamino-4-phenyl-cyclohexanecarbonitril
[0297] 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
[0298] 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
[0299] 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)
[0300] 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), 5 g, Diluent: MeOH, Mobile phase: A)
0.05% TFA in water; B) ACN flow rate: 1 ml/min, Rt=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-1071:
CIS-8-(dimethylamino)-8-phenyl-1-(2,2,2-trifluoroethyl)-1,3-diazaspiro[4.-
5]decan-2-one
##STR00045##
[0301] Step 1: tert-butyl
CIS-2-(8-(dimethylamino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)ace-
tate
[0302] To a solution of
CIS-8-dimethylamino-8-phenyl-1,3-diaza-spiro[4.5]decan-2-one
(INT-976) (10.0 g, 36.63 mmol, 1.0 eq.) in dry THF (1.5 L) was
added potassium tert-butoxide (7.14 mg, 36.63 mmol, 1.1 eq.) at RT.
The reaction mixture was stirred for 30 min followed by addition of
tert-butyl bromo acetate (4.51 g, 40.293 mmol, 1.1 eq.). The
reaction mixture was stirred at RT for 4 h, poured into ice-water
and extracted with EtOAc (2.times.700 mL). The organic layer was
washed with water (400 mL), brine (400 mL) and dried over
Na.sub.2SO.sub.4 and concentrated under reduced pressure. The
resulting crude product was purified by column chromatography
(neutral alumina; 1% MeOH/Hexane) to yield
CIS-(8-dimethylamino-2-oxo-8-phenyl-1,3-diaza-spiro[4.5]dec-3-yl)-acetic
acid tert-butyl ester (7 g, 18.06 mmol, 49%) as a white solid.
LC-MS: m/z [M+1].sup.+=387.9 (MW calc.=387.52).
Step 2: mixture of
CIS-(1-cyclopropylmethyl-8-dimethylamino-2-oxo-8-phenyl-1,3-diaza-spiro[4-
.5]dec-3-yl)-acetic acid cyclopropylmethyl ester and
CIS-(1-cyclopropylmethyl-8-dimethylamino-2-oxo-8-phenyl-1,3-diaza-spiro[4-
.5]dec-3-yl)-acetic acid tert-butyl ester
[0303] To a solution of
CIS-(8-dimethylamino-2-oxo-8-phenyl-1,3-diaza-spiro[4.5]dec-3-yl)-acetic
acid tert-butyl ester (2.0 g, 5.16 mmol, 1.0 eq.) in dry DMF (40
mL) was added 60 wt % NaH (413 mg, 10.33 mmol, 2 eq.) at RT. The
reaction mixture was stirred for 30 min followed by addition of
bromomethylcyclopropane (1.74 g, 12.91 mmol, 2.5 eq.). The reaction
mixture was stirred at RT for 20 h, poured slowly into ice-water
and extracted with EtOAc (2.times.400 mL). The organic layer was
washed with water (2.times.200 mL), brine (200 mL) and dried over
Na.sub.2SO.sub.4 and concentrated under reduced pressure to get
crude product which was purified by column chromatography (neutral
alumina; 30% EA/Hexane) to yield a mixture of
CIS-(1-cyclopropylmethyl-8-dimethylamino-2-oxo-8-phenyl-1,3-diaza-spiro[4-
.5]dec-3-yl)-acetic acid cyclopropylmethyl ester and
CIS-(1-cyclopropylmethyl-8-dimethylamino-2-oxo-8-phenyl-1,3-diaza-spiro[4-
.5]dec-3-yl)-acetic acid tert-butyl ester (3:2) (1.1 g, 2.505 mmol,
48%) as a light brown sticky liquid. LC-MS: m/z [M+1].sup.+=440.0,
442.0 (MW calc.=439.59, 441.61).
Step 3:
CIS-2-(1-cyclopropylmethyl-8-dimethylamino-2-oxo-8-phenyl-1,3-diaz-
a-spiro[4.5]dec-3-yl)-acetamide
[0304] To a mixture of
CIS-(1-cyclopropylmethyl-8-dimethylamino-2-oxo-8-phenyl-1,3-diaza-spiro[4-
.5]dec-3-yl)-acetic acid cyclopropylmethyl ester and
CIS-(1-cyclopropylmethyl-8-dimethylamino-2-oxo-8-phenyl-1,3-diaza-spiro[4-
.5]dec-3-yl)-acetic acid tert-butyl ester (2.0 g, 4.55 mmol, 1.0
eq.) in dry MeOH (5 mL) was added 7M NH.sub.3 in MeOH (15 mL) and
the reaction mixture was stirred in a sealed tube at 95.degree. C.
for 48 h. Solvent was evaporated under reduced pressure to get
crude product which was purified by column chromatography (neutral
alumina; 2% MeOH/DCM) to yield
CIS-2-(1-cyclopropylmethyl-8-dimethylamino-2-oxo-8-phenyl-1,3-diaza-spiro-
[4.5]dec-3-yl)-acetamide (1.2 g, 3.15 mmol, 68%) as an off-white
solid. LC-MS (Method 1): m/z [M+H].sup.+=385.2 (MW
calc.=384.52).
Step 4:
CIS-(1-cyclopropylmethyl-8-dimethylamino-2-oxo-8-phenyl-1,3-diaza--
spiro[4.5]dec-3-yl) acetonitrile (INT-1071)
[0305] To a solution of
CIS-2-(1-cyclopropylmethyl-8-dimethylamino-2-oxo-8-phenyl-1,3-diaza-spiro-
[4.5]dec-3-yl)-acetamide (1.7 g, 4.42 mmol, 1.0 eq.) in dry DMF (40
mL) was added cyanuric chloride (2.4 g, 13.28 mmol, 3 eq.) at RT.
The reaction mixture was stirred at RT for 1.5 h, basified
(pH.about.9) with sat. aq. NaHCO.sub.3 and extracted with EtOAc
(2.times.400 mL). The combined organic layer was washed with water
(2.times.300 mL), brine (300 mL), dried over Na.sub.2SO.sub.4 and
concentrated under reduced pressure to get crude product which was
purified by column chromatography (neutral alumina; 80% DCM/Hexane)
to yield
CIS-(1-cyclopropylmethyl-8-dimethylamino-2-oxo-8-phenyl-1,3-diaza-spiro[4-
.5]dec-3-yl) acetonitrile (1.1 g, 3.00 mmol, 68%) as an off-white
solid. LC-MS: m/z [M+1].sup.+=367.3 (MW calc.=366.50).
[0306] 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 in analogy m/z Intermediate Chemical Name Chemical
Structure to method [M + H].sup.+ INT-794
CIS-3-(3,4-dimethoxybenzyl)- 8-(dimethylamino)-8-phenyl-
1,3-diazaspiro[4.5]decan-2-one ##STR00046## 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 ##STR00047##
INT-974 390.3 INT-797 CIS-8-(Ethyl-methyl-amino)-8- phenyl-1,3-
diazaspiro[4.5]decan-2-one ##STR00048## INT-976 288.2 INT-949
CIS-8-Dimethylamino-1-ethyl- 8-phenyl-1,3-
diazaspiro[4.5]decan-2-one ##STR00049## 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 ##STR00050##
INT-952 432.3 INT-954 4-Dimethylamino-4-(5-methyl-
thiophen-2-yl)-cyclohexan-1- one ##STR00051## INT-965 238.1 INT-955
4-Dimethylamino-4-thiophen- 2-yl-cyclohexan-1-one ##STR00052##
INT-965 224.1 INT-956 1-(1-Methyl-1H-pyrazol-3-yl)-
4-oxo-cyclohexane-1- carbonitrile ##STR00053## INT-958 204.1
INT-957 4-Oxo-1-pyrazin-2-yl- cyclohexane-1-carbonitrile
##STR00054## INT-958 202.1 INT-959 4-Dimethylamino-4-(1-methyl-
1H-pyrazol-3-yl)-cyclohexan- 1-one ##STR00055## INT-961 222.2
INT-960 4-Dimethylamino-4-pyrazin-2- yl-cyclohexan-1-one
##STR00056## INT-961 220.1 INT-962 4-Dimethylamino-4-(3-
methoxyphenyl)-cyclohexan-1- one ##STR00057## INT-965 248.2 INT-963
CIS-3-Benzyl-8- dimethylamino-8-phenyl-1,3-
diazaspiro[4.5]decan-2-one ##STR00058## INT-975 364.2 INT-964
4-(Ethyl-methyl-amino)-4- phenyl-cyclohexan-1-one ##STR00059##
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 ##STR00060## 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
##STR00061## 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 ##STR00062##
INT-971 478.3 INT-970 CIS-8-Dimethylamino-8-(4-
methoxyphenyl)-3-[(4- methoxyphenyl)-methyl]-1,3-
diazaspiro[4.5]decan-2-one ##STR00063## SC_2017 424.3 INT-972
CIS-8-Dimethylamino-8-(3- methoxyphenyl)-3-[(4-
methoxyphenyl)-methyl]-1,3- diazaspiro[4.5]decan-2-one ##STR00064##
SC_2017 424.3 INT-973 CIS-8-Dimethylamino-8-(4-
fluorophenyl)-3-[(4- methoxyphenyl)-methyl]-1,3-
diazaspiro[4.5]decan-2-one ##STR00065## INT-974 412.2 INT-979
CIS-8-Dimethylamino-1-(3- methoxy-propyl)-8-phenyl-1,3-
diazaspiro[4.5]decan-2-one ##STR00066## INT-984 346.2 INT-980
CIS-8-Dimethylamino-1-(2- methoxy-ethyl)-8-phenyl-1,3-
diazaspiro[4.5]decan-2-one ##STR00067## INT-984 332.2 INT-981
CIS-8-Dimethylamino-8- phenyl-1-propyl-1,3-
diazaspiro[4.5]decan-2-one ##STR00068## INT-984 316.2 INT-983
CIS-1-(Cyclopropyl-methyl)-8- dimethylamino-8-phenyl-1,3-
diazaspiro[4.5]decan-2-one ##STR00069## INT-984 328.2 INT-985
CIS-1-(Cyclobutyl-methyl)-8- (methyl-propyl-amino)-8- phenyl-1,3-
diazaspiro[4.5]decan-2-one ##STR00070## INT-986 370.3 INT-993
4-benzyl-4- (dimethylamino)cyclohexanone ##STR00071## INT-965 232.3
INT-994 CIS-8-benzyl-8- (dimethylamino)-1,3-
diazaspiro[4.5]decan-2-one ##STR00072## INT-976 288.2 INT-995
TRANS-8-benzyl-8- (dimethylamino)-1,3- diazaspiro[4.5]decan-2-one
##STR00073## INT-976 288.2 INT-997 CIS-8-(dimethylamino)-8-
(thiophen-2-yl)-1,3- diazaspiro[4.5]decan-2-one ##STR00074##
INT-976 280.1 INT-998 TRANS-8-(dimethylamino)-8-
(thiophen-2-yl)-1,3- diazaspiro[4.5]decan-2-one ##STR00075##
INT-976 280.1 INT-999 4-(dimethylamino)-4-(1-
methyl-1H-benzo[d]imidazol- 2-yl)cyclohexanone ##STR00076## 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
##STR00077## 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 ##STR00078## INT-976 328.2 INT-1009
TRANS-8-ethylamino-8- phenyl-1,3-diaza- spiro[4.5]decan-2-one
##STR00079## INT-1008 274.2 INT-1024 CIS-8-(dimethylamino)-8-(3-
fluorophenyl)-1,3- diazaspiro[4.5]decan-2-one ##STR00080## INT-977
(step 2) 292.2 INT-1025 CIS-8-(dimethylamino)-8-(4-
fluorophenyl)-1,3- diazaspiro[4.5]decan-2-one ##STR00081##
INT-974,.sub. INT-977 (step 2) 292.2 INT-1039
CIS-8-(dimethylamino)-8-(3- (trifluoromethoxy)phenyl)-1,3-
diazaspiro[4.5]decan-2-one ##STR00082## INT-1038 358.2 INT-1040
(CIS)-8-(dimethylamino)-8-(3- (trifluoromethyl)phenyl)-1,3-
diazaspiro[4.5]decan-2-one ##STR00083## INT-1038 342.2 INT-1041
(CIS)-8-(dimethylamino)-8-(3- methoxyphenyl)-1,3-
diazaspiro[4.5]decan-2-one ##STR00084## INT-1038 304.2 INT-1042
(CIS)-8-(5-chlorothiophen-2- yl)-8-(dimethylamino)-1,3-
diazaspiro[4.5]decan-2-one ##STR00085## INT-1038 314.1 INT-1043
(CIS)-8-(dimethylamino)-8-(3- fluoro-5-methylphenyl)-1,3-
diazaspiro[4.5]decan-2-one ##STR00086## INT-1038 306.2 INT-1044
(CIS)-8-(3-chlorophenyl)-8- (dimethylamino)-1,3-
diazaspiro[4.5]decan-2-one ##STR00087## INT-1038 308.2 INT-1047
(CIS)-8-(methyl(oxetan-3- ylmethyl)amino)-8-phenyl-1,3-
diazaspiro[4.5]decan-2-one ##STR00088## INT-1026 330.5 INT-1050
(CIS)-8-(dimethylamino)-8- phenyl-3-(piperidin-4-yl)-1,3-
diazaspiro[4.5]decan-2-one ##STR00089## SC_4054 357.3 INT-1051
(CIS)-8-(dimethylamino)-8- phenyl-3-(piperidin-4- ylmethyl)-1,3-
diazaspiro[4.5]decan-2-one ##STR00090## SC_4058 371.5 INT-1053
(CIS)-3-(2-amino-2- methylpropyl)-8- (dimethylamino)-1-((1-
hydroxycyclobutyl)methyl)-8- phenyl-1,3- diazaspiro[4.5]decan-2-one
##STR00091## INT-1052 429.3 INT-1061 TRANS-1-(cyclopropyl-
methyl)-8-dimethylamino-8- phenyl-1,3- diazaspiro[4.5]decan-2-one
##STR00092## INT-984 328.2 INT-1063 CIS-1-(cyclopropylmethyl)-8-
(dimethylamino)-8-(3- fluorophenyl)-1,3- diazaspiro[4.5]decan-2-one
##STR00093## INT-1031 346.2 INT-1066 TRANS-1-(cyclobutylmethyl)-
8-(dimethylamino)-8-phenyl- 1,3-diazaspiro[4.5]decan-2-one
##STR00094## INT-987 342.3 INT-1070 CIS-8-(dimethylamino)-8-
phenyl-1-(3,3,3- trifluoropropyl)-1,3- diazaspiro[4.5]decan-2-one
##STR00095## INT-1068 360.2 INT-1072 CIS-8-(dimethylamino)-1-((1-
hydroxycyclobutyl)methyl)-8- phenyl-3-(piperidin-4-yl)-1,3-
diazaspiro[4.5]decan-2-one ##STR00096## SC_4054 441.3 INT-1073
CIS-8-(dimethylamino)-1-((1- hydroxycyclobutyl)methyl)-8-
phenyl-3-(piperidin-4-yl)-1,3- diazaspiro[4.5]decan-2-one
##STR00097## SC_4054 429.3 INT-1074 CIS-8-(dimethylamino)-8-(3-
fluorophenyl)-1-((1- hydroxycyclobutyl)methyl)-
1,3-diazaspiro[4.5]decan-2-one ##STR00098## INT-1031 376.2
Synthesis of Exemplary Compounds
Synthesis of SC_4001:
CIS-4-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspir-
o[4.5]decan-3-yl]-butyramide
##STR00099##
[0308]
CIS-4-[1-(cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-dia-
zaspiro[4.5]decan-3-yl]-butyronitrile (SC_4012) (201 mg, 0.5 mmol)
was dissolved in DMSO (7 mL) and K.sub.2CO.sub.3 (136 mg, 1 mmol)
and hydrogen peroxide (30% in water, 0.7 mL) were added. The
resulting mixture was stirred at RT for 18 h, then quenched with 2N
aq. NaOH (5 mL) and extracted with ethyl acetate (3.times.5 mL).
The combined organic layers were dried over Na.sub.2SO.sub.4,
concentrated in vacuo and purified by flash chromatography to yield
CIS-4-[1-(cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspir-
o[4.5]decan-3-yl]-butyramide SC_4001 (58 mg) as a white solid.
[M+H].sup.+ 427.3
Synthesis of SC_4003:
CIS-1-(Cyclobutyl-methyl)-8-dimethylamino-3-[2-[2-(2-methoxy-ethoxy)-etho-
xy]-ethyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one
##STR00100##
[0310] In an oven dried flask, sodium hydroxide powder (28 mg, 0.7
mmol) was added to DMSO (0.25 mL) at RT. The mixture was stirred
for 5 min, then
CIS-1-(cyclobutyl-methyl)-8-dimethylamino-8-phenyl-1,3-diazaspiro[4.-
5]decan-2-one (INT-987) (60 mg, 0.18 mmol) was added and the
reaction mixture was stirred for 10 min at RT.
1-[2-(2-Bromo-ethoxy)ethoxy]-2-methoxy-ethane (120 mg, 0.53 mmol)
was added and the resulting mixture was stirred for 30 min at RT
and for 2 h at 60.degree. C. Water was added and the aqueous layer
was extracted with DCM (3.times.10 mL). The combined organic layers
were dried over Na.sub.2SO.sub.4 and concentrated in vacuo. The
residue was purified by flash chromatography to yield
CIS-1-(cyclobutyl-methyl)-8-dimethylamino-3-[2-[2-(2-methoxy-ethoxy)-etho-
xy]-ethyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one (SC_4003) (38
mg) as a white solid. [M+H].sup.+ 488.3
Synthesis of SC_4010:
CIS-1-(Cyclobutyl-methyl)-8-methylamino-3-(2-methylsulfonyl-ethyl)-8-phen-
yl-1,3-diazaspiro[4.5]decan-2-one
##STR00101##
[0312] N-Iodosuccinimide (30 mg, 0.14 mmol) was added to a
suspension of
CIS-1-(cyclobutyl-methyl)-8-dimethylamino-3-(2-methylsulfonyl-ethyl)-8-ph-
enyl-1,3-diazaspiro[4.5]decan-2-one (SC_4009) (40 mg, 0.09 mmol) in
a mixture of acetonitrile and THF (1:1 v/v, 20 mL) at RT and the
resultant 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 under
reduced pressure. 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.
The residue was purified by flash chromatography and prep. HPLC to
give 16 mg of
CIS-1-(cyclobutyl-methyl)-8-methylamino-3-(2-methylsulfonyl-ethyl)-8-phen-
yl-1,3-diazaspiro[4.5]decan-2-one (SC_4010). [M+H].sup.+ 434.2
Synthesis of SC_4012:
CIS-4-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-[1,3-diazaspi-
ro[4.5]decan-3-yl]-butyronitrile
##STR00102##
[0314] Potassium cyanide (131 mg, 2 mmol) and sodium iodide (202
mg, 1.4 mmol) were added to a solution of
CIS-3-(3-chloro-propyl)-1-(cyclobutyl-methyl)-8-dimethylamino-8-phenyl-1,-
3-diazaspiro[4.5]decan-2-one (SC_4027) (57 mg, 1.4 mmol) in DMSO (5
mL) at RT and the resulting mixture was stirred at 90.degree. C.
for 18 h. The reaction mixture was quenched with water (5 mL) and
extracted with ethyl acetate (5.times.25 mL). The combined organic
layers were dried over Na.sub.2SO.sub.4 and concentrated in vacuo.
The residue was purified by flash chromatography to yield
CIS-4-[1-(cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspir-
o[4.5]decan-3-yl]-butyronitrile (SC_4012) (38 mg) as a white solid.
[M+H].sup.+ 409.3
Synthesis of SC_4013:
CIS-4-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspir-
o[4.5]decan-3-yl]-N-methyl-butyramide
##STR00103##
[0316]
CIS-4-[1-(cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-dia-
zaspiro[4.5]decan-3-yl]-butyric acid methyl ester (SC_4028) (59 mg,
0.13 mmol) was treated with 2M methylamine in methanol (1.5 mL) and
heated for 100 min at 100.degree. C. in a closed vessel. Volatiles
were removed under a stream of nitrogen, the residue was taken up
in 2M methylamine in methanol (1.5 mL) and heated for 50 min at
120.degree. C. in a closed vessel. All volatiles were removed under
a stream of nitrogen to afford the crude product, which was
purified by column chromatography to yield 49 mg of
CIS-4-[1-(cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3--
diazaspiro[4.5]decan-3-yl]-N-methyl-butyramide (SC_4013) as a white
solid. [M+H].sup.+ 441.3
Synthesis of SC_4025:
CIS-8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-8-phenyl-3-(tetrahy-
dro-pyran-4-yl-methyl)-1,3-diazaspiro[4.5]decan-2-one
##STR00104##
[0318] KOtBu (1M in THF) (0.5 mL, 0.504 mmol) was added to a
suspension of
CIS-8-dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-8-phenyl-1,3-diazas-
piro[4.5]decan-2-one (INT-799) (0.15 g, 0.42 mmol) in THF (4 mL) at
0.degree. C. The reaction mixture was stirred for 10 min and a
solution of 4-(bromomethyl)tetrahydro-2H-pyran (90 mg, 0.504 mmol)
in THF (2 mL) was added. The reaction mixture was stirred at
70.degree. C. for 16 h, then quenched with sat. aq. NH.sub.4Cl (5
mL) and extracted with ethyl acetate (2.times.20 mL). The combined
organic extracts were washed with water, brine, dried over anhydr.
Na.sub.2SO.sub.4 and concentrated under reduced pressure. The
residue was purified by preparative TLC to afford 0.044 g of
CIS-8-dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-8-phenyl-3-(tetrahy-
dro-pyran-4-yl-methyl)-1,3-diazaspiro[4.5]decan-2-one (SC_4025) as
an off-white solid (TLC system: 10% MeOH in DCM R.sub.f: 0.52.).
[M+H].sup.+ 456.3
Synthesis of SC_4027:
CIS-3-(3-Chloro-propyl)-1-(cyclobutyl-methyl)-8-dimethylamino-8-phenyl-1,-
3-diazaspiro[4.5]decan-2-one
##STR00105##
[0320] Sodium hydride (60% suspension in mineral oil, 23 mg, 0.6
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) (100 mg, 0.3 mmol) in THF (3 mL) at 0.degree. C.
and the resulting mixture was stirred for 30 min at 50.degree. C. A
solution of 1-bromo-3-chloro-propane (0.14 mL, 1.5 mmol) in THF
(0.7 mL) was added at 50.degree. C. and stirring was continued at
80.degree. C. for 18 h. The reaction mixture was quenched with cold
water (10 mL) and extracted with ethyl acetate (3.times.10 mL). The
combined organic layers were dried over Na.sub.2SO.sub.4 and
concentrated in vacuo. The residue was purified by flash
chromatography to yield
CIS-3-(3-chloro-propyl)-1-(cyclobutyl-methyl)-8-dimethylamino-8-phenyl-1,-
3-diazaspiro[4.5]decan-2-one (SC_4027) (50 mg) as a white powder.
[M+H].sup.+ 418.3
Synthesis of SC_4028:
CIS-4-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspir-
o[4.5]decan-3-yl]-butyric acid methyl ester
##STR00106##
[0322]
CIS-4-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-dia-
zaspiro[4.5]decan-3-yl]-butyronitrile SC_4012 (345 mg, 0.85 mmol)
was dissolved in 5 mL conc. HCl and stirred for 6 h at 100.degree.
C. Volatiles were removed under reduced pressure to afford the
crude product as hydrochloride salt. This salt was dissolved in
MeOH/toluene and concentrated under reduced pressure. The latter
dissolution/evaporation cycle was repeated, yielding 380 mg of
CIS-4-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspir-
o[4.5]decan-3-yl]-butyric acid methyl ester SC_4028. [M+H].sup.+
442.
Synthesis of SC_4031:
CIS-3-acetyl-8-(dimethylamino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one
##STR00107##
[0324] To the mixture of
CIS-8-dimethylamino-8-phenyl-1,3-diaza-spiro[4.5]decan-2-one
(INT-976) (3.5 g, 12.83 mmol, 1.0 eq.) and K.sub.2CO.sub.3 (3.54 g,
25.66 mmol, 2.0 eq.) in THF (200 ml) at 0.degree. C. was added
acetyl chloride (1.4 ml, 19.23 mmol, 1.5 eq.). The reaction mixture
was stirred at RT for 3 h, diluted with DCM (300 ml) and filtered
through Celite. The filtrate was washed with sat. aq. NaHCO.sub.3
(100 ml), water (100 ml) and brine (100 ml). The organic layer was
dried over Na.sub.2SO.sub.4 and concentrated under reduced
pressure. The resulting residue was purified by column
chromatography (silica gel neutralized with ammonia, 5% MeOH/DCM)
to yield
CIS-3-acetyl-8-dimethylamino-8-phenyl-1,3-diaza-spiro[4.5]decan-2-o-
ne (SC-4031) as an off white solid. Note: This reaction was done in
two parallel batches of 3.5 g scale and yield given for two
combined batches. Yield: 63% (5.1 g, 16.19 mmol). .sup.1HNMR
(DMSO-d6, 400 MHz), .delta. (ppm)=8.05 (bs, 1H), 7.36-7.25 (m, 5H),
3.44 (s, 2H), 2.31 (s, 5H, CH.sub.3+CH.sub.2), 1.92 (s, 6H),
1.83-1.76 (m, 4H), 1.39 (bs, 2H). Mass: m/z 316.1 [M+H].sup.+
Synthesis of SC_4032:
CIS-8-(dimethylamino)-3-(2-(methylsulfonyl)ethyl)-8-phenyl-1,3-diazaspiro-
[4.5]decan-2-one
##STR00108##
[0326] KOtBu (1M in THF) (1.1 mL, 0.11 mmol) was added to the
suspension of
CIS-8-(dimethylamino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one
(INT-976) (0.3 g, 0.11 mmol) in THF (10 mL) at 0.degree. C. The
reaction mixture was stirred for 10 min and
1-bromo-2-(methylsulfonyl)ethane (0.16 g, 0.09 mmol) was added. The
reaction mixture was stirred at 0.degree. C. for 4 h, then quenched
with sat. aq. NH.sub.4Cl (15 mL) and the organic product was
extracted with DCM (3.times.20 mL). The combined organic extracts
were washed with brine, dried over anhydr. Na.sub.2SO.sub.4 and
concentrated under reduced pressure. Purification of the residue by
reverse phase preparative HPLC afforded 180 mg (43%) of
CIS-8-(dimethylamino)-3-(2-(methylsulfonyl)ethyl)-8-phenyl-1,3-diazaspiro-
[4.5]decan-2-one (SC_4032) as an off white solid (TLC system: 10%
MeOH in DCM Rf: 0.3.). .sup.1H NMR (DMSO-d6): .delta. 7.37-7.23 (m,
5H), 6.90 (br s, 1H), 3.43 (t, 2H), 3.26 (t, 2H), 3.10 (s, 2H),
2.95 (s, 3H), 2.32 (br m, 2H), 1.93 (s, 6H), 1.79-1.76 (m, 4H),
1.38-1.36 (m, 2H). Mass: m/z 380.2 [M+H].sup.+
Synthesis of SC_4033:
CIS-1-acetyl-8-(dimethylamino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one
##STR00109##
[0327] Step 1:
CIS-1-acetyl-8-(dimethylamino)-3-(4-methoxybenzyl)-8-phenyl-1,3-diazaspir-
o[4.5]decan-2-one
[0328] To a solution of
CIS-8-dimethylamino-3-(4-methoxy-benzyl)-8-phenyl-1,3-diaza-spiro[4.5]dec-
an-2-one (INT-975) (19.5 g, 49.6 mmol, 1.0 eq.) in THF (180 ml) was
added 2.5M solution of n-BuLi in hexane (39.7 ml, 99.23 mmol, 2.0
eq.) at 0.degree. C. and the resulting mixture was stirred for 1 h.
A solution of acetyl chloride (7.7 g, 99.23 mmol, 2.0 eq.) in THF
(20 ml) was added dropwise at 0.degree. C. The cooling bath was
removed, the reaction mixture was stirred at RT for 16 h, then
cooled down to 0.degree. C. again, quenched with water and
extracted with ethyl acetate (2.times.200 ml). The combined organic
extracts were washed with brine (250 ml), dried over
Na.sub.2SO.sub.4 and concentrated under reduced pressure. The
residue was purified by column chromatography (silica gel; 30%
EtOAc/Hexane) to yield
CIS-1-acetyl-8-dimethylamino-3-(4-methoxy-benzyl)-8-phenyl-1,3-diaza-spir-
o[4.5]decan-2-one (6.1 g, 14.02 mmol, 28%) as a light yellow sticky
solid. Mass: m/z 436.3 [M+H].sup.+
Step 2:
CIS-1-acetyl-8-(dimethylamino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-
-one (SC_4033)
[0329] To a solution of
CIS-1-acetyl-8-dimethylamino-3-(4-methoxy-benzyl)-8-phenyl-1,3-diaza-spir-
o[4.5]decan-2-one (5.0 g, 11.5 mmol, 1.0 eq.) in acetonitrile (60
ml) was added a solution cerium(IV) ammonium nitrate (18.98 g, 34.5
mmol, 3.0 eq.) in water (60 ml) at 0.degree. C. and the reaction
mixture was stirred at RT for 2 h. The reaction mixture was
quenched with aq. NaHCO.sub.3 solution (50 ml) and extracted with
ethyl acetate (2.times.100 ml). The combined organic layer was
washed with brine (2.times.100 ml), dried over Na.sub.2SO.sub.4 and
concentrated under reduced pressure. The residue was purified by
column chromatography (silica gel neutralized with TEA; 2/3 v/v
EtOAc/Hexane) to yield
CIS-1-acetyl-8-dimethylamino-8-phenyl-1,3-diaza-spiro[4.5]decan-2-one
(SC_4033) as an off white solid. Yield: 61% (4.9 g, 15.55 mmol).
.sup.1HNMR (DMSO-d6, 400 MHz), .delta. (ppm)=7.57 (s, 1H),
7.33-7.23 (m, 5H), 3.21 (s, 2H), 3.03 (t, 2H, J=12.78 Hz), 2.60 (d,
2H, J=13.32 Hz), 2.32 (s, 3H), 1.89 (s, 6H), 1.37-1.32 (m, 4H).
Mass: m/z 316.2 [M+H].sup.+
Synthesis of SC_4034:
CIS-1-(cyclopropylmethyl)-8-(dimethylamino)-3-(2-(methylsulfonyl)ethyl)-8-
-phenyl-1,3-diazaspiro[4.5]decan-2-one
##STR00110##
[0331] To a solution of
CIS-8-dimethylamino-3-(2-methanesulfonyl-ethyl)-8-phenyl-1,3-diaza-spiro[-
4.5]decan-2-one (SC_4032) (150 mg, 0.395 mmol, 1.0 eq.) in dry DMF
(5 ml) was added 60% NaH (47 mg, 1.18 mmol, 3.0 eq.) at RT and the
reaction mixture was stirred for 20 min. Bromomethylcyclopropane
(160 mg, 1.18 mmol, 3.0 eq.) was added and the reaction mixture was
stirred for 16 h. The reaction mixture was quenched with ice-water
(20 ml) and extracted with EtOAc (2.times.20 ml). The combined
organic layers were washed with water (20 ml) and brine (20 ml),
dried over anhydr. Na.sub.2SO.sub.4 and concentrated under reduced
pressure. The residue was purified by column chromatography (silica
gel; 3% MeOH/DCM) to yield
CIS-1-cyclopropylmethyl-8-dimethylamino-3-(2-methanesulfonyl-ethyl)-8-phe-
nyl-1,3-diaza-spiro[4.5]decan-2-one (80 mg, 0.18 mmol, 47%)
(SC_4034) as a white solid. .sup.1HNMR (CDCl3, 400 MHz), .delta.
(ppm)=7.36-7.24 (m, 5H, merged with CDCl3), 3.65 (t, 2H, J=6.46
Hz), 3.27 (t, 2H, J=6.46 Hz), 3.23 (s, 2H), 3.04 (d, 2H, J=6.7 Hz),
2.94 (s, 3H), 2.65-2.62 (m, 2H), 2.30-2.23 (m, 2H), 2.02 (s, 6H),
1.46-1.40 (m, 4H), 1.02-0.98 (m, 1H), 0.53-0.49 (m, 2H), 0.33-0.29
(2H). Mass: m/z 434.0 (M+H).sup.+ (MW calc.=433.61).
Synthesis of SC_4037:
CIS-8-(dimethylamino)-8-phenyl-1-tosyl-1,3-diazaspiro[4.5]decan-2-one
##STR00111##
[0332] Step 1:
CIS-8-(dimethylamino)-3-(4-methoxybenzyl)-8-phenyl-1-tosyl-1,3-diazaspiro-
[4.5]decan-2-one
[0333]
CIS-8-(dimethylamino)-3-[(4-methoxyphenyl)methyl]-8-phenyl-1,3-diaz-
aspiro[4.5]decan-2-one (INT-975) (500 mg, 1.271 mmol) was dissolved
in THF (8 mL) under nitrogen atmosphere and the solution was cooled
down to -78.degree. C. [Bis(trimethylsilyl)amino]lithium (1M in
THF, 1.5 equiv., 1.906 mmol, 1.9 mL) was added dropwise and the
reaction mixture was stirred at -78.degree. C. for 30 min, then at
0.degree. C. for 30 min. The reaction mixture was cooled down to
-78.degree. C. again and the solution of p-toluenesulfonyl chloride
(1.5 equiv., 1.906 mmol) in THF (5 mL) was added. The reaction
mixture was stirred further 2.5 h at -78.degree. C. and then the
temperature was allowed to increase to RT overnight. The reaction
mixture was quenched by the addition of sat. aq. NaHCO.sub.3 (20
mL). The aqueous phase was extracted with EtOAc (3.times.40 mL).
The combined organic extracts were washed with brine (30 mL), dried
over MgSO.sub.4 and concentrated under reduced pressure.
Purification of the residue by flash chromatography on silica gel
(elution with gradient DCM/EtOH 100/0 to 97/3) yielded 281 mg (40%)
of
CIS-8-(dimethylamino)-3-(4-methoxybenzyl)-8-phenyl-1-tosyl-1,3-diazaspiro-
[4.5]decan-2-one. .sup.1H NMR (600 MHz, DMSO) .delta. 7.90-7.84 (m,
2H), 7.47-7.40 (m, 2H), 7.42-7.27 (m, 4H), 7.27-7.22 (m, 1H),
7.15-7.06 (m, 2H), 6.92-6.83 (m, 2H), 4.16 (s, 2H), 3.72 (s, 3H),
3.24 (s, 2H), 2.99 (ddd, 2H), 2.70-2.62 (m, 2H), 2.42 (s, 3H), 2.01
(s, 6H), 1.56-1.49 (m, 2H), 1.31 (td, 2H). Mass: m/z 548.3
(M+H).sup.+.
Step 2:
CIS-8-(dimethylamino)-8-phenyl-1-tosyl-1,3-diazaspiro[4.5]decan-2--
one (SC_4037)
[0334] In analogy to the method described for INT-982 (step 2)
CIS-8-(dimethylamino)-3-(4-methoxybenzyl)-8-phenyl-1-tosyl-1,3-diazaspiro-
[4.5]decan-2-one was reacted with trifluoroacetic acid to be
converted into
CIS-8-(dimethylamino)-8-phenyl-1-tosyl-1,3-diazaspiro[4.5]decan-2-on-
e (SC_4037). .sup.1HNMR (DMSO-d6, 400 MHz), .delta. (ppm)=7.82 (d,
2H, J=8.0 Hz), 7.48 (s, 1H), 7.40 (d, 2H, J=7.88 Hz), 7.35-7.24 (m,
5H), 3.27 (s, 2H), 2.97 (t, 2H, J=11.88 Hz), 2.66 (d, 2H, J=12.76
Hz), 2.39 (s, 3H), 2.0 (s, 6H), 1.60 (d, 2H, J=11.04 Hz), 1.38 (t,
2H, J=13.56 Hz). Mass: m/z 427.9 (M+H).sup.+.
Synthesis of SC_4038:
CIS-8-(dimethylamino)-3-((1,1-dioxidotetrahydro-2H-thiopyran-4-yl)methyl)-
-1-((1-hydroxycyclobutyl)methyl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one
##STR00112##
[0335] Step 1:
CIS-8-(dimethylamino)-1-((1-hydroxycyclobutyl)methyl)-8-phenyl-3-((tetrah-
ydro-2H-thiopyran-4-yl)methyl)-1,3-diazaspiro[4.5]decan-2-one
[0336] NaH (60% in mineral oil) (84.03 mg, 2.101 mmol) was added to
an ice cold solution of
CIS-8-(methylamino)-8-phenyl-3-(2-(trifluoromethyl)pyrimidin-5-yl)-1,3-di-
azaspiro[4.5]decan-2-one (INT-799) (500 mg, 1.401 mmol) in DMF (5
mL) under argon atmosphere and the resulting mixture was stirred
for 2 min. The reaction mixture was allowed to warm up to RT and a
solution of (tetrahydro-2H-thiopyran-4-yl)methyl
4-methylbenzenesulfonate (481.5 mg, 1.681 mmol) in DMF (4.8 mL) was
added. The reaction mixture was stirred at RT for 16 h. The
reaction progress was monitored by LCMS. The reaction mixture was
diluted with water (50 mL) and the organic product was extracted
with EtOAc (3.times.40 mL). The combined organic extracts were
dried over anhydrous Na.sub.2SO.sub.4 and concentrated under
reduced pressure to give 550 mg of crude product. The crude product
was purified by prep-HPLC (column LUNA-PHENYL HEXYL-C.sub.18
(150*30 mm) 5 .mu.m, detection at 215 nm, eluent 10 mM ammonium
bicarbonate in water/Acetonitrile gradient 45/55 to 2/98, flow
rate: 25 ml/min) to afford 235 mg (35%) of
CIS-8-(dimethylamino)-1-((1-hydroxycyclobutyl)methyl)-8-phenyl-3-((tetrah-
ydro-2H-thiopyran-4-yl)methyl)-1,3-diazaspiro[4.5]decan-2-one as an
off white solid (TLC system: 5% MeOH in DCM Rf: 0.63.). Mass: m/z
472.3 (M+H)+.
Step 2:
CIS-8-(dimethylamino)-3-((1,1-dioxidotetrahydro-2H-thiopyran-4-yl)-
methyl)-1-((1-hydroxycyclobutyl)methyl)-8-phenyl-1,3-diazaspiro[4.5]decan--
2-one (SC_4038)
[0337] A solution of oxone (599.53 mg, 0.975 mmol) in water (6 mL)
was added to a solution of
CIS-8-(dimethylamino)-1-((1-hydroxycyclobutyl)methyl)-8-phenyl-3-((tetrah-
ydro-2H-thiopyran-4-yl)methyl)-1,3-diazaspiro[4.5]decan-2-one (230
mg, 0.488 mmol) in MeOH (8 mL) at RT under argon atmosphere. The
reaction mixture was stirred for 16 h. The reaction progress was
monitored by LCMS. The reaction mixture was filtered and the
filtrate was concentrated under reduced pressure to give 330 mg of
crude product, which was purified by prep. HPLC (column LUNA-PHENYL
HEXYL-C18 (150*30 mm) 5 .mu.m, detection at 215 nm, eluent 10 mM
ammonium bicarbonate in water/Acetonitrile gradient 45/55 to 2/98,
flow rate: 25 ml/min) to get 128 mg (52%) of
CIS-8-(dimethylamino)-3-(4-(bromomethyl)-1-.lamda.6-thiane-1,1-dione)-1-(-
(1-hydroxycyclobutyl)methyl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one
(SC_4038) as an off white solid (TLC system: 10% MeOH in DCM Rf:
0.53). .sup.1H NMR (DMSO-d6): .delta. 7.37-7.25 (m, 5H), 6.01 (s,
1H), 3.26 (s, 2H), 3.09-2.99 (m, 8H), 2.69-2.65 (m, 2H), 2.09-1.82
(m, 15H), 1.66-1.51 (m, 3H), 1.41-1.33 (m, 5H). Mass: m/z 504.2
(M+H).sup.+.
Synthesis of SC_4044:
CIS-8-(dimethylamino)-1-((1-hydroxycyclobutyl)methyl)-3-((4-hydroxytetrah-
ydro-2H-pyran-4-yl)methyl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one
##STR00113##
[0339] NaH (0.14 g, 3.501 mmol, 60% dispersion in mineral oil) was
added to a solution of
CIS-8-(dimethylamino)-1-((1-hydroxycyclobutyl)methyl)-8-phenyl-1,3-diazas-
piro[4.5]decan-2-one (INT-799) (0.25 g, 0.700 mmol) in THF (40 mL)
at 0.degree. C. under argon atmosphere. The solution of
1,6-dioxaspiro[2.5]octane (0.479 g, 4.200 mmol) in THF (2 mL) was
added dropwise and the reaction mixture was stirred at 85.degree.
C. for 16 h. The reaction mixture was cooled to 0.degree. C. and
quenched with water (50 mL). The organic product was extracted with
ethyl acetate (2.times.50 mL). Combined organic layer was dried
over anhydrous Na.sub.2SO.sub.4 and concentrated under reduced
pressure. The residue was purified by column chromatography (silica
gel 230-400 mesh size, 0-60% EtOAc in pet ether as eluent) followed
by reverse phase prep HPLC to get 0.180 g of
CIS-8-(dimethylamino)-1-((1-hydroxycyclobutyl)methyl)-3-((4-hydroxytetrah-
ydro-2H-pyran-4-yl)methyl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one
formate. The product formate salt was taken in water (20 mL),
basified with solid NaHCO.sub.3 and extracted with ethyl acetate
(2.times.20 mL). The combined organic layer was dried over
anhydrous Na.sub.2SO.sub.4 and concentrated under reduced pressure
to afford 0.130 g (39%) of
CIS-8-(dimethylamino)-1-((1-hydroxycyclobutyl)methyl)-3-((4-hydroxytetrah-
ydro-2H-pyran-4-yl)methyl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one
(SC_4044) as an off white solid. (TLC system: 5% MeOH in DCM; Rf:
0.3). .sup.1H NMR (DMSO-d6): .delta. 7.37-7.34 (m, 4H), 7.27-7.26
(m, 1H), 6.04 (s, 1H), 4.51 (s, 1H), 3.61-3.56 (m, 4H), 3.43 (s,
2H), 3.09-3.05 (m, 4H), 2.70-2.67 (m, 2H), 2.07-1.82 (m, 12H),
1.63-1.61 (m, 1H), 1.51-1.30 (m, 9H). Mass: m/z 472.3
(M+H).sup.+.
Synthesis of SC_4049:
CIS-(5s,8s)-3-(1-benzoylpiperidin-4-yl)-1-(cyclopropylmethyl)-8-(dimethyl-
amino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one
##STR00114##
[0341] Triethylamine (0.51 mL, 3.65 mmol) was added to a stirred
solution of
CIS-1-(cyclopropylmethyl)-8-(dimethylamino)-8-phenyl-3-(piperidin-4-yl-
)-1,3-diazaspiro[4.5]decan-2-one hydrochloride (0.3 g, 0.73 mmol)
in DCM (10 mL) at 0.degree. C. under argon atmosphere. After 10
min, acetyl chloride (86 mg, 1.09 mmol) was added dropwise at
0.degree. C. and the reaction mixture was stirred at RT for 16 h.
The reaction mixture was quenched with sat. aq. NaHCO.sub.3. The
organic product was extracted with DCM (2.times.50 mL), the
combined organic layer was dried over anhydr. Na.sub.2SO.sub.4 and
concentrated under reduced pressure. The residue was purified by
reverse phase prep. HPLC to afford 0.133 g (40%) of
CIS-3-(1-acetylpiperidin-4-yl)-1-(cyclopropylmethyl)-8-(dimethylamino)-
-8-phenyl-1,3-diazaspiro[4.5]decan-2-one (SC_4049) as a white
solid. (TLC system: 10% MeOH in DCM; Rf: 0.55). .sup.1H NMR
(DMSO-d6): .delta. 7.36-7.33 (m, 2H), 7.28-7.25 (m, 3H), 4.70-4.67
(m, 1H), 3.98-3.81 (m, 2H), 3.12-3.04 (m, 5H), 2.65-2.57 (m, 3H),
2.26 (t, 2H), 2.06-2.04 (m, 9H), 1.79-1.70 (m, 2H), 1.50-1.39 (m,
6H), 1.02 (m, 1H), 0.53-0.50 (m, 2H), 0.34-0.31 (m, 2H). Mass: m/z
453.3 (M+H).sup.+.
Synthesis of SC_4052:
CIS-1-(cyclobutylmethyl)-8-(dimethylamino)-3-(2-(1-hydroxycyclohexyl)ethy-
l)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one
##STR00115##
[0342] Step 1:
CIS-3-(2-(1-(benzyloxy)cyclohexyl)ethyl)-1-(cyclobutylmethyl)-8-(dimethyl-
amino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one
[0343] In analogy to the method described for SC_4034
CIS-1-(cyclobutylmethyl)-8-(dimethylamino)-8-phenyl-1,3-diazaspiro[4.5]de-
can-2-one (INT-787) was reacted with
2-(4-(benzyloxy)tetrahydro-2H-pyran-4-yl)ethyl
4-methylbenzenesulfonate to be converted into
CIS-3-(2-(1-(benzyloxy)cyclohexyl)ethyl)-1-(cyclobutylmethyl)-8-(dimethyl-
amino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one. Mass: m/z 558.4
(M+H).sup.+.
Step 2:
CIS-1-(cyclobutylmethyl)-8-(dimethylamino)-3-(2-(1-hydroxycyclohex-
yl)ethyl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one (SC_4052)
[0344] Trifluoroacetic acid (20 mL) was added to
CIS-3-(2-(1-(benzyloxy)cyclohexyl)ethyl)-1-(cyclobutylmethyl)-8-(dimethyl-
amino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one (0.4 g, 0.71 mmol)
at RT. The reaction mixture was stirred at RT for 16 h and then
concentrated under reduced pressure. To the residue sat. aq.
NaHCO.sub.3 was added and the organic product was extracted with
dichloromethane (3.times.150 mL). The combined organic extract was
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; 4-8% MeOH in DCM as eluent) and further
by reverse phase prep HPLC to afford 0.112 g (40%) of
CIS-1-(cyclobutylmethyl)-8-(dimethylamino)-3-(2-(1-hydroxycyclohexyl)ethy-
l)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one (SC_4052) as a white
solid. (TLC system: 10% MeOH in DCM; Rf: 0.45). .sup.1H NMR
(DMSO-d6): .delta. 7.37-7.32 (m, 4H), 7.27-7.23 (m, 1H), 4.25 (s,
1H), 3.62-3.49 (m, 4H), 3.17-3.13 (m, 2H), 3.09 (s, 2H), 3.01 (d,
2H), 2.66-2.63 (m, 2H), 2.05-2.02 (m, 1H), 1.97-1.91 (m, 9H),
1.80-1.65 (m, 4H), 1.53-1.43 (m, 5H), 1.38-1.35 (m, 6H). Mass: m/z
470.4 (M+H).sup.+.
Synthesis of SC_4054:
CIS-1-(cyclopropylmethyl)-8-(dimethylamino)-8-phenyl-3-(piperidin-4-yl)-1-
,3-diazaspiro[4.5]decan-2-one
##STR00116##
[0345] Step 1: CIS-tert-butyl
4-(1-(cyclopropylmethyl)-8-(dimethylamino)-2-oxo-8-phenyl-1,3-diazaspiro[-
4.5]decan-3-yl)piperidine-1-carboxylate
[0346] In analogy to the method described for SC_4044
CIS-1-(cyclopropylmethyl)-8-(dimethylamino)-8-phenyl-1,3-diazaspiro[4.5]d-
ecan-2-one (INT-983) was reacted with tert-butyl
4-(tosyloxy)piperidine-1-carboxylate to be converted into
CIS-tert-butyl
4-(1-(cyclopropylmethyl)-8-(dimethylamino)-2-oxo-8-phenyl-1,3-diazaspiro[-
4.5]decan-3-yl)piperidine-1-carboxylate. Mass: m/z 511.4
(M+H).sup.+.
Step 2:
CIS-1-(cyclopropylmethyl)-8-(dimethylamino)-8-phenyl-3-(piperidin--
4-yl)-1,3-diazaspiro[4.5]decan-2-one (SC_4054)
[0347] 4N HCl in dioxane (20 mL) was added to a solution of
CIS-tert-butyl
4-(1-(cyclopropylmethyl)-8-(dimethylamino)-2-oxo-8-phenyl-1,3-diazaspiro[-
4.5]decan-3-yl)piperidine-1-carboxylate (1.9 g, 3.7 mmol) in DCM
(30 mL) at 0.degree. C. under argon atmosphere. The reaction was
stirred at 0.degree. C. for 2 h and then concentrated under reduced
pressure to get
CIS-1-(cyclopropylmethyl)-8-(dimethylamino)-8-phenyl-3-(piperidin-4-yl)-1-
,3-diazaspiro[4.5]decan-2-one hydrochloride as gummy, which was
triturated with diethyl ether to get
CIS-1-(cyclopropylmethyl)-8-(dimethylamino)-8-phenyl-3-(piperidin-4-yl)-1-
,3-diazaspiro[4.5]decan-2-one hydrochloride (SC_4054) as an
off-white solid. (TLC system: 10% MeOH in DCM; Rf: 0.15). .sup.1H
NMR (DMSO-d6): .delta. 7.37-7.32 (m, 4H), 7.28-7.23 (m, 1H),
3.58-3.50 (m, 2H), 3.10 (s, 2H), 2.94-2.89 (m, 4H), 2.66-2.62 (m,
2H), 2.46-2.41 (m, 2H), 2.13 (t, 2H), 1.97 (s, 6H), 1.49-1.41 (m,
6H), 1.32-1.29 (m, 2H), 0.93-0.88 (m, 1H), 0.46-0.42 (m, 2H),
0.25-0.24 (m, 2H). Mass: m/z 411.3 (M+H).sup.+.
Synthesis of SC_4055:
CIS-1-(cyclopropylmethyl)-8-(dimethylamino)-3-(2-hydroxy-2-methylpropyl)--
8-phenyl-1,3-diazaspiro[4.5]decan-2-one
##STR00117##
[0348] Step 1: tert-butyl
2-(CIS-1-(cyclopropylmethyl)-8-(dimethylamino)-2-oxo-8-phenyl-1,3-diazasp-
iro[4.5]decan-3-yl)acetate
[0349] In analogy to the method described for SC_4027
CIS-1-(cyclopropylmethyl)-8-(dimethylamino)-8-phenyl-1,3-diazaspiro[4.5]d-
ecan-2-one (INT-983) was reacted with tert-butyl bromoacetate to be
converted into tert-butyl
2-(CIS-1-(cyclopropylmethyl)-8-(dimethylamino)-2-oxo-8-phenyl-1,3-diazasp-
iro[4.5]decan-3-yl)acetate. Mass: m/z 442.3 (M+H).sup.+.
Step 2: methyl
CIS-2-(1-(cyclopropylmethyl)-8-(dimethylamino)-2-oxo-8-phenyl-1,3-diazasp-
iro[4.5]decan-3-yl)acetate
[0350] 4M HCl in dioxane (8 mL) was added to tert-butyl
CIS-2-(1-(cyclopropylmethyl)-8-(dimethylamino)-2-oxo-8-phenyl-1,3-diazasp-
iro[4.5]decan-3-yl)acetate (800 mg, 1.81 mmol) in DCM (6 mL) at
0.degree. C. The reaction mixture was stirred at RT for 16 h and
then concentrated under reduced pressure. The residue was suspended
in DCM and the resulting mixture was concentrated under reduced
pressure again. The residue was washed with diethyl ether (5 mL) to
give
CIS-2-(8-(dimethylamino)-3-oxo-8-phenyl-2-azaspiro[4,5]decan-2-yl)acetic
acid hydrochloride which was dissolved in methanol (10 mL) and
refluxed for 2 h. The reaction mixture was cooled down to RT and
concentrated under reduced pressure. The residue was partitioned
between EtOAc and sat. aq. NaHCO.sub.3. The organic layer was
separated and washed with water, brine, dried over anhydr.
Na.sub.2SO.sub.4 and concentrated under reduced pressure.
Purification of the residue by column chromatography (silica gel
100-200 mesh, 0-3% MeOH in DCM) yielded 500 mg (56%) of methyl
CIS-2-(1-(cyclopropylmethyl)-8-(dimethylamino)-2-oxo-8-phenyl-1,3--
diazaspiro[4.5]decan-3-yl)acetate as a solid. (TLC system: 10% MeOH
in DCM Rf: 0.20). Mass: m/z 400.3 (M+H).sup.+.
Step 3:
CIS-1-(cyclopropylmethyl)-8-(dimethylamino)-3-(2-hydroxy-2-methylp-
ropyl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one (SC_4055)
[0351] Methylmagnesium bromide (3M in Et.sub.2O, 2.1 mL, 6.25 mmol)
was added to a solution of methyl
CIS-2-(1-(cyclopropylmethyl)-8-(dimethylamino)-2-oxo-8-phenyl-1,3-diazasp-
iro[4.5]decan-3-yl)acetate (500 mg, 1.25 mmol) in THF (10 mL) at
0.degree. C. The reaction mixture was warmed to RT and stirred for
2 h. The reaction mixture was quenched with sat. aq. NH.sub.4Cl and
the organic product was extracted with DCM (3.times.25 mL). The
combined organic extracts were washed with water, brine, dried over
anhydr. Na.sub.2SO.sub.4 and concentrated under reduced pressure.
Purification of the resulting residue by column chromatography
(silica gel 100-200 mesh, 0-3% MeOH in DCM) followed by preparative
HPLC yielded 80 mg (16%) of
CIS-1-(cyclopropylmethyl)-8-(dimethylamino)-3-(2-hydroxy-2-methylpropyl)--
8-phenyl-1,3-diazaspiro[4.5]decan-2-one (SC_4055) as a solid. (TLC
system: 10% MeOH in DCM Rf: 0.20).
[0352] .sup.1H NMR (DMSO d6): .delta. 7.36-7.33 (m, 4H), 7.26-7.24
(m, 1H), 4.39 (s, 1H), 3.30 (m, 2H), 2.95-2.91 (m, 4H), 2.69-2.66
(m, 2H), 2.18-2.13 (m, 2H), 1.97 (s, 6H), 1.37-1.31 (m, 4H), 1.03
(s, 6H), 0.92-0.91 (m, 1H), 0.46-0.43 (m, 2H), 0.26-0.23 (m, 2H).
Mass: m/z 400.3 (M+H).sup.+.
Synthesis of SC_4056:
CIS-1-(cyclopropylmethyl)-8-(dimethylamino)-8-phenyl-3-(1-(pyrimidin-5-yl-
)piperidin-4-yl)-1,3-diazaspiro[4.5]decan-2-one
##STR00118##
[0354] CsCO.sub.3 (1.27 g, 3.90 mmol) was added to a solution of
CIS-1-(cyclopropylmethyl)-8-(dimethylamino)-8-phenyl-3-(piperidin-4-yl)-1-
,3-diazaspiro[4.5]decan-2-one hydrochloride (SC_4054) (0.4 g, 0.97
mmol), XanthPhos (85 mg, 0.146 mmol), Pd.sub.2(dba).sub.3 (89 mg,
0.097 mmol) and 5-bromopyrimidine (0.31 g, 1.95 mmol) in
1,4-dioxane (20 mL). The mixture was purged with argon for 5 min
and then stirred for 16 h at 120.degree. C. The reaction mixture
was cooled to RT and concentrated under reduced pressure. The
residue was diluted with DCM (20 mL), filtered through a pad of
celite and concentrated under reduced pressure. The crude product
was purified by flash chromatography (silica gel 230-400 mesh size,
5-10% methanol in DCM as eluent) to afford 0.4 g of the desired
product, which was further purified by reverse phase prep HPLC to
afford 172 mg (36%) of
CIS-1-(cyclopropylmethyl)-8-(dimethylamino)-8-phenyl-3-(1-(pyrimidin-5-yl-
)piperidin-4-yl)-1,3-diazaspiro[4.5]decan-2-one (SC_4056) as
off-white solid. (TLC system: 10% MeOH in DCM; Rf: 0.35). .sup.1H
NMR (CDCl3): .delta. 8.64 (s, 1H), 8.34 (s, 2H), 7.36-7.33 (m, 2H),
7.29-7.27 (m, 2H), 7.24 (m, 1H), 4.00-3.96 (m, 1H), 3.78-3.76 (m,
2H), 3.09-3.06 (m, 4H), 2.96-2.90 (m, 2H), 2.66-2.63 (m, 2H),
2.30-2.24 (m, 2H), 2.04 (s, 6H), 1.83-1.81 (m, 2H), 1.73-1.61 (m,
2H), 1.45-1.40 (m, 4H), 1.04-1.01 (m, 1H), 0.54-0.50 (m, 2H),
0.35-0.32 (m, 2H). Mass: m/z 489.3 (M+H).sup.+.
Synthesis of SC_4057:
CIS-1-(cyclopropylmethyl)-8-(dimethylamino)-8-phenyl-3-(1-(pyrimidin-5-yl-
)piperidin-4-yl)-1,3-diazaspiro[4.5]decan-2-one
##STR00119##
[0356] Triethylamine (0.23 mL, 1.70 mmol) was added to a solution
of
CIS-1-(cyclopropylmethyl)-8-(dimethylamino)-8-phenyl-3-(piperidin-4-yl)-1-
,3-diazaspiro[4.5]decan-2-one hydrochloride (SC_4054) (0.35 g, 0.85
mmol) and phenylboronic acid (0.21 g, 1.70 mmol) in acetonitrile
(15 mL). Copper(II) acetate (155 mg, 0.85 mmol) was added and the
reaction mixture was stirred at 100.degree. C. for 24 h. The
reaction mixture was cooled to RT, filtered through a pad of celite
and concentrated under reduced pressure. The residue was purified
by silica gel flash chromatography (3% MeOH/DCM) to give 100 mg of
CIS-1-(cyclopropylmethyl)-8-(dimethylamino)-8-phenyl-3-(1-phenylpiperidin-
-4-yl)-1,3-diazaspiro[4.5]decan-2-one, which was further purified
by reverse phase prep HPLC to afford 38 mg (9%) of
CIS-1-(cyclopropylmethyl)-8-(dimethylamino)-8-phenyl-3-(1-phenylpiperidin-
-4-yl)-1,3-diazaspiro[4.5]decan-2-one (SC_4057) as an off-white
solid. (TLC system: 10% MeOH in DCM; Rf: 0.65). .sup.1H NMR
(DMSO-d6): .delta. 7.36-7.33 (m, 2H), 7.29-7.27 (m, 2H), 7.24-7.21
(m, 3H), 6.91 (d, 2H), 6.81 (t, 1H), 3.95-3.91 (m, 1H), 3.72-3.69
(m, 2H), 3.11-3.06 (m, 4H), 2.84-2.79 (m, 2H), 2.65-2.62 (m, 2H),
2.26 (t, 2H), 2.04 (s, 6H), 1.79-1.70 (m, 4H), 1.45-1.40 (m, 4H),
1.05-1.01 (m, 1H), 0.53-0.51 (m, 2H), 0.34-0.32 (m, 2H). Mass: m/z
487.4 (M+H).sup.+.
Synthesis of SC_4064:
CIS-3-((1-aminocyclopropyl)methyl)-1-(cyclopropylmethyl)-8-(dimethylamino-
)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one
##STR00120##
[0358] To a solution titanium isopropoxide (0.89 mL, 3.0 mmol, 2
eq.) in dry THF (15 mL) was added EtMgBr (3 M in Et.sub.2O) (2 mL,
6.0 mmol, 4 eq.) at -78.degree. C. and the resulting mixture was
stirred for 1.5 h at -78.degree. C. A solution of
CIS-(1-cyclopropylmethyl-8-dimethylamino-2-oxo-8-phenyl-1,3-diaza-spiro[4-
.5]dec-3-yl)-acetonitrile (INT-1071) (550 mg, 1.50 mmol, 1.0 eq.)
in THF (5 mL) was added dropwise at -78.degree. C. The reaction
mixture was stirred at same temperature for 10 min, then warmed to
RT and stirred for 1.5 h. The reaction mixture was cooled again to
-78.degree. C., BF.sub.3.Et.sub.2O (0.37 mL, 3.0 mmol, 2 eq.) was
added and the resulting mixture was stirred at -78.degree. C. for
10 min and at RT for 1.5 h. The reaction mixture was basified
(pH-9-10) with 10 wt % aq. NaOH, stirred for 30 min and extracted
with EtOAc (2.times.250 mL). The combined organic layer was washed
with water (2.times.150 mL), brine (200 mL), dried over
Na.sub.2SO.sub.4 and concentrated under reduced pressure to get
crude product which was purified by column chromatography (neutral
alumina; 2.5% MeOH/DCM) to yield
CIS-3-(1-amino-cyclopropylmethyl)-1-cyclopropylmethyl-8-dimethylamino-8-p-
henyl-1,3-diaza-spiro[4.5]decan-2-one (SC_4064) as off white solid.
This step was done in two batches of 550 mg scale and yield is
given for combined batches. Yield: 16% (200 g, 0.25 mmol). LC-MS:
m/z [M+H].sup.+=397.1 (MW calc.=396.57). .sup.1HNMR (DMSO-d.sub.6,
400 MHz), .delta. (ppm)=7.35-7.25 (5H), 3.24 (s, 2H), 3.00 (s, 2H),
2.92 (d, 2H, J=6.48 Hz), 2.68-2.65 (m, 2H), 2.19-2.07 (m, 2H), 1.97
(s, 6H), 1.75 (bs, 2H), 1.43-1.36 (m, 4H), 0.93 (bs, 1H), 0.46-0.36
(m, 6H), 0.25-0.23 (m, 2H).
Synthesis of SC_4071:
CIS-1-(cyclobutylmethyl)-8-(dimethylamino)-3-(2-(3-hydroxyoxetan-3-yl)eth-
yl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one
##STR00121##
[0359] Step 1: 2-(3-(benzyloxy)oxetan-3-yl)acetaldehyde
[0360] To a stirred solution of 3-allyl-3-(benzyloxy)oxetane (10.0
g, 49.01 mmol, prepared from 3-allyl-3-hydroxyoxetane and benzyl
bromide) in acetone (300 mL) and water (200 mL) was added potassium
osmate(VI) dihydrate (0.61 g, 1.66 mmol). The reaction mixture was
cooled to 0.degree. C. and sodium periodate (41.93 g, 916.07 mmol)
was added portionwise over a period of 15 min. The reaction mixture
was allowed to stir for 1 h at 0.degree. C. The reaction mixture
was filtered and the filter cake was washed with acetone (300 mL).
The combined filtrate was concentrated under reduced pressure and
the aqueous layer was extracted with dichloromethane (2.times.300
mL). The combined organic layer was washed with water (2.times.200
mL), brine (300 mL), dried was over anhydr. Na.sub.2SO.sub.4 and
concentrated under reduced pressure. The resulting crude product
was purified by column chromatography (silica gel 230-400 mesh size
30-40% EtOAc in Pet. ether as eluent) to afford
2-(3-(benzyloxy)oxetan-3-yl)acetaldehyde (4.5 g, 43%) as a liquid.
(TLC system: 40% EtOAc in Pet. ether; Rf: 0.4).
Step 2: 2-(3-(benzyloxy)oxetan-3-yl)ethanol
[0361] To a cold stirred solution of
2-(3-(benzyloxy)oxetan-3-yl)ethanol (4.50 g, 21.84 mmol) in
methanol (50 mL) was added portionwise NaBH.sub.4 (1.24 g, 32.76
mmol). The reaction mixture was stirred at 0.degree. C. for 1 h.
The reaction mixture was quenched with water (30 mL), concentrated
under reduced pressure and the residue was taken in DCM (150 mL).
The organic layer was washed with water (100 mL) and brine (100
mL), dried over anhydr. Na.sub.2SO.sub.4 and concentrated under
reduced pressure to get 5.0 g of crude
2-(3-(benzyloxy)oxetan-3-yl)ethanol which was used in the next step
without further purification.
Step 3: 2-(3-(benzyloxy)oxetan-3-yl)ethyl
4-methylbenzenesulfonate
[0362] To a stirred solution of 2-(3-(benzyloxy)oxetan-3-yl)ethanol
(5.0 g, 24.03 mmol) in DCM (15 mL) were added triethylamine (13.4
mL, 96.15 mmol) and DMAP (0.29 g, 2.40 mmol). The reaction mixture
was cooled to 0.degree. C. and tosyl chloride (9.13 g, 48.07 mmol)
was added to the reaction mixture portionwise. The reaction mixture
was stirred at RT for 16 h, then diluted with sat. aq. NaHCO.sub.3
and the organic product was extracted with DCM (200 mL). The
organic layer was dried over anhydr. Na.sub.2SO.sub.4 and
concentrated under reduced pressure. The resulting crude product
was purified by column chromatography (230-400 mesh silica gel;
20-40% EtOAc in Pet. ether as eluent) to afford
2-(3-(benzyloxy)oxetan-3-yl)ethyl 4-methylbenzenesulfonate (4.0 g,
50% over 2 steps) as an off-white solid.
Step 4:
CIS-3-(2-(3-(benzyloxy)oxetan-3-yl)ethyl)-1-(cyclobutylmethyl)-8-(-
dimethylamino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one
[0363] NaH (0.29 g, 7.33 mmol, 60% dispersion in mineral oil) was
added to a solution of
CIS-1-(cyclobutylmethyl)-8-(dimethylamino)-8-phenyl-1,3-diazaspiro[4.5]de-
can-2-one (INT-987) (0.50 g, 1.46 mmol) in DMF (15 mL) at RT under
argon atmosphere and the resulting mixture was stirred for 10 min.
2-(3-(Benzyloxy)oxetan-3-yl)ethyl 4-methylbenzenesulfonate (1.58 g,
4.39 mmol) was added and the reaction mixture was stirred at
120.degree. C. for 16 h. The reaction progress was monitored by
LCMS. The reaction mixture was cooled to 0.degree. C. and quenched
with sat. aq. NaHCO.sub.3 (50 mL). The organic product was
extracted with DCM (2.times.100 mL), the combined organic phase was
dried over anhydr. Na.sub.2SO.sub.4 and concentrated under reduced
pressure. The resulting crude product was purified by flash
chromatography (silica gel 230-400 mesh size 2-5% methanol in DCM
as eluent) to afford 0.40 g (51%) of
CIS-3-(2-(3-(benzyloxy)oxetan-3-yl)ethyl)-1-(cyclobutylmethyl)-8-(dimethy-
lamino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one as a brown oil.
(TLC system: 10% MeOH in DCM; Rf: 0.6).
Step 5:
CIS-1-(cyclobutylmethyl)-8-(dimethylamino)-3-(2-(3-hydroxyoxetan-3-
-yl)ethyl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one (SC_4071)
[0364]
CIS-3-(2-(3-(benzyloxy)oxetan-3-yl)ethyl)-1-(cyclobutylmethyl)-8-(d-
imethylamino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one (0.38 g, 0.71
mmol) in THF (4 mL) was added to sodium metal (0.32 g, 14.31 mmol)
in liquid ammonia (5 mL) at -78.degree. C. The reaction mixture was
stirred for 20 min at -78.degree. C., then quenched with saturated
NH.sub.4Cl solution and the organic product was extracted with
EtOAc (2.times.20 mL). The combined organic layer was dried over
anhydr. Na.sub.2SO.sub.4 and concentrated under reduced pressure.
The resulting crude product was purified by flash chromatography
(silica gel 230-400 mesh 2-5% methanol in DCM as eluent) to afford
0.155 g (49%) of
CIS-1-(cyclobutylmethyl)-8-(dimethylamino)-3-(2-(3-hydroxyoxetan-3-yl)eth-
yl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one (SC_4071) as an
off-white solid. (TLC system: 5% MeOH in DCM; Rf: 0.4). .sup.1H NMR
(DMSO-d6): .delta. 7.36-7.32 (m, 4H), 7.26-7.23 (m, 1H), 5.62 (s,
1H), 4.38-4.31 (m, 4H), 3.14-3.10 (m, 4H), 3.01 (d, 2H), 2.64-2.63
(m, 2H), 2.49 (m, 1H), 2.02-1.96 (m, 10H), 1.87-1.77 (m, 6H), 1.39
(t, 2H), 1.28 (d, 2H). Mass: m/z 442.3 (M+H).sup.+.
Synthesis of SC_4072:
CIS-1-(cyclopropylmethyl)-8-(dimethylamino)-3-(2-methyl-2-(2-oxopyrrolidi-
n-1-yl)propyl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one
##STR00122##
[0365] Step 1:
CIS-4-chloro-N-(1-(1-(cyclopropylmethyl)-8-(dimethylamino)-2-oxo-8-phenyl-
-1,3-diazaspiro[4.5]decan-3-yl)-2-methylpropan-2-yl)butanamide
[0366] In analogy to the method described for SC_4049
CIS-3-(2-amino-2-methylpropyl)-1-(cyclopropylmethyl)-8-(dimethylamino)-8--
phenyl-1,3-diazaspiro[4.5]decan-2-one (INT-1052) was reacted with
4-chlorobutanoyl chloride to be converted into
CIS-4-chloro-N-(1-(1-(cyclopropylmethyl)-8-(dimethylamino)-2-oxo-8-phenyl-
-1,3-diazaspiro[4.5]decan-3-yl)-2-methylpropan-2-yl)butanamide.
Mass: m/z 503.3 (M+H).sup.+.
Step 2:
CIS-1-(cyclopropylmethyl)-8-(dimethylamino)-3-(2-methyl-2-(2-oxopy-
rrolidin-1-yl)propyl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one
(SC_4072)
[0367] NaH (60% in mineral oil) (95.62 mg, 2.390 mmol) was added to
a solution of
CIS-4-chloro-N-(1-(1-(cyclopropylmethyl)-8-(dimethylamino)-2-oxo-8-phenyl-
-1,3-diazaspiro[4.5]decan-3-yl)-2-methylpropan-2-yl)butanamide (0.3
g, 0.598 mmol) in THF (30 mL) at 0.degree. C. under argon
atmosphere. The reaction mixture was stirred at 70.degree. C. for 4
h, then cooled to 0.degree. C. and quenched with water (15 mL). The
organic product was extracted with EtOAc (2.times.30 mL). The
combined organic extracts were dried over anhydr. Na.sub.2SO.sub.4
and concentrated under reduced pressure. The resulting crude
product was purified by column chromatography (silica gel 230-400
mesh, 0-10% MeOH in DCM) and reverse phase HPLC to yield 80 mg
(28%) of
CIS-1-(cyclopropylmethyl)-8-(dimethylamino)-3-(2-methyl-2-(2-oxopyrrolidi-
n-1-yl)propyl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one (SC_4072) as
a white solid (TLC system: 5% MeOH in DCM; Rf: 0.30). .sup.1H NMR
(DMSO-d6): .delta. 7.37-7.32 (m, 4H), 7.27-7.24 (m, 1H), 3.34-3.27
(m, 4H), 3.16-3.13 (m, 4H), 2.93 (d, 2H), 2.67-2.64 (m, 2H),
2.16-2.05 (m, 4H), 1.97 (s, 6H), 1.40-1.36 (m, 4H), 1.29 (s, 6H),
0.93-0.92 (m, 1H), 0.46-0.44 (m, 2H), 0.26-0.24 (m, 2H). Mass: m/z
503.3 (M+H).sup.+.
Synthesis of SC_4080:
CIS-8-(dimethylamino)-8-phenyl-3-(1-phenylpiperidin-4-yl)-1,3-diazaspiro[-
4.5]decan-2-one
##STR00123##
[0369] KOtBu (94.26 mg, 0.840 mmol) was added to a solution of
CIS-8-(dimethylamino)-8-phenyl-3-(piperidin-4-yl)-1,3-diazaspiro[4.5]deca-
n-2-one (INT-1050) (0.25 g, 0.70 mmol), bromobenzene (109.9 mg,
0.70 mmol), BINAP (65.38 mg, 0.105 mmol) and Pd.sub.2(dba).sub.3
(96.15 mg, 0.105 mmol) in toluene (40 mL). The mixture was purged
with argon for 5 min and stirred for 16 h at 90.degree. C. The
reaction mixture was cooled to RT and diluted with DCM (20 mL),
filtered through a pad of celite and the filtrate was concentrated
under reduced pressure. The resulting crude product was purified by
flash chromatography (silica gel 230-400 mesh, 5-10% methanol in
DCM as eluent) followed by reverse phase prep. HPLC to afford 57 mg
(18%) of
CIS-8-(dimethylamino)-8-phenyl-3-(1-phenylpiperidin-4-yl)-1,3-diazaspiro[-
4.5]decan-2-one (SC_4080) as an off-white solid. (TLC system: 10%
MeOH in DCM; Rf: 0.40). Reverse prep HPLC condition: mobile phase:
10 mM ammonium bicarbonate in H.sub.2O/acetonitrile; column:
INERTSIL-ODS(250*19 mm) 5 .mu.m; gradient (% B): 0/65, 8/80,
8.1/98, 12/98, 12.1/65, 15/65; flow rate: 18 ml/min; diluent:
ACN+THF+MeOH+H.sub.2O. .sup.1H NMR (DMSO-d6): .delta. 7.36-7.30 (m,
4H), 7.23 (t, 1H), 7.18-7.14 (m, 2H), 6.90 (d, 2H), 6.72 (t, 2H),
3.72-3.69 (m, 2H), 3.65-3.60 (m, 1H), 3.01 (s, 2H), 2.70-2.65 (m,
2H), 2.28 (br s, 2H), 1.93 (s, 6H), 1.78 (br m, 4H), 1.68-1.60 (m,
2H), 1.57-1.55 (m, 2H), 1.34-1.31 (m, 2H). Mass: m/z 433.3
(M+H).sup.+.
Synthesis of SC_4084:
CIS-1-(1-(1-(cyclopropylmethyl)-8-(dimethylamino)-2-oxo-8-phenyl-1,3-diaz-
aspiro[4.5]decan-3-yl)-2-methylpropan-2-yl)pyrrolidine-2,5-dione
##STR00124##
[0370] Step 1:
CIS-4-(1-(1-(cyclopropylmethyl)-8-(dimethylamino)-2-oxo-8-phenyl-1,3-diaz-
aspiro[4.5]decan-3-yl)-2-methylpropan-2-ylamino)-4-oxobutanoic
acid
[0371] Succinic anhydride (233.3 mg, 2.330 mmol) was added to a
stirred solution of
CIS-3-(2-amino-2-methylpropyl)-1-(cyclopropylmethyl)-8-(dimethylamino)-8--
phenyl-1,3-diazaspiro[4.5]decan-2-one (0.58 g, 1.457 mmol) in DCM
(15 mL) at RT under argon atmosphere. The reaction mixture was
stirred at RT for 4 h and then concentrated under reduced pressure
to yield 440 mg of crude
CIS-4-(1-(1-(cyclopropylmethyl)-8-(dimethylamino)-2-oxo-8-phenyl-1,3-diaz-
aspiro[4.5]decan-3-yl)-2-methylpropan-2-ylamino)-4-oxobutanoic acid
as an off-white solid (TLC system: 5% MeOH in DCM; Rf: 0.35).
Step 2:
CIS-1-(1-(1-(cyclopropylmethyl)-8-(dimethylamino)-2-oxo-8-phenyl-1-
,3-diazaspiro[4.5]decan-3-yl)-2-methylpropan-2-yl)pyrrolidine-2,5-dione
(SC_4084)
[0372] Acetyl chloride (2.2 mL) was added to a solution of
CIS-4-(1-(1-(cyclopropylmethyl)-8-(dimethylamino)-2-oxo-8-phenyl-1,3-diaz-
aspiro[4.5]decan-3-yl)-2-methylpropan-2-ylamino)-4-oxobutanoic acid
(0.44 g, 0.883 mmol) in EtOAc (30 mL) at 0.degree. C. under argon
atmosphere. The reaction mixture was stirred at 80.degree. C. for
16 h. The reaction mixture was cool to RT, concentrated under
reduced pressure, quenched with sat. aq. NaHCO.sub.3 and the
organic product was extracted with EtOAc (2.times.30 mL). The
combined organic extracts were dried over anhydrous
Na.sub.2SO.sub.4 and concentrated under reduced pressure. The
resulting crude product was purified by column chromatography
(silica gel 230-400 mesh, 0-8% MeOH in DCM) followed by reverse
phase prep HPLC to get 50 mg (9%) of
CIS-1-(1-(1-(cyclopropylmethyl)-8-(dimethylamino)-2-oxo-8-phenyl-1,3-diaz-
aspiro[4.5]decan-3-yl)-2-methylpropan-2-yl)pyrrolidine-2,5-dione
(SC_4084) as a white solid (TLC system: 5% MeOH in DCM; Rf: 0.30).
Reverse prep HPLC condition: mobile phase: 10 mM ammonium
bicarbonate in H.sub.2O/acetonitrile; column: INERTSIL-ODS(250*19
mm) 5 .mu.m; gradient (% B): 0/80, 9/90, 9.1/80, 12/80; flow rate:
18 ml/min; diluent: ACN+THF+H.sub.2O.
[0373] .sup.1H NMR (DMSO-d6): .delta. 7.35-7.34 (m, 4H), 7.27-7.24
(m, 1H), 3.34 (s, 2H), 3.19 (s, 2H), 2.87 (d, 2H), 2.66-2.64 (m,
2H), 2.43 (s, 4H), 2.13-2.08 (m, 2H), 1.97 (s, 6H), 1.51 (s, 6H),
1.37-1.32 (m, 4H), 0.89-0.87 (m, 1H), 0.45-0.42 (m, 2H), 0.27-0.24
(m, 2H). Mass: m/z 481.3 (M+H).sup.+.
Synthesis of SC_4096:
CIS-1-(cyclopropylmethyl)-8-(dimethylamino)-8-phenyl-3-(1-(pyridazin-4-yl-
)piperidin-4-yl)-1,3-diazaspiro[4.5]decan-2-one
##STR00125##
[0374] Step 1:
CIS-3-(1-(6-chloropyridazin-4-yl)piperidin-4-yl)-1-(cyclopropylmethyl)-8--
(dimethylamino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one
[0375] DIPEA (0.566 g, 4.3 mmol) was added to a solution of
CIS-1-(cyclopropylmethyl)-8-(dimethylamino)-8-phenyl-3-(piperidin-4-yl)-1-
,3-diazaspiro[4.5]decan-2-one (SC_4054) (0.6 g, 1.4 mmol) and
3,5-dichloropyridazine (310 mg, 2.10 mmol) in
N-methyl-2-pyrrolidone (30 mL). The reaction mixture was purged
with argon for 10 min and stirred for 16 h at 80.degree. C. The
reaction mixture was quenched with water and extracted with EtOAc
(3.times.20 mL). The combined organic layer was concentrated under
reduced pressure and the crude product was purified by flash
chromatography (silica gel 230-400 mesh size, 5-10% methanol in
dichloromethane as eluent) to afford 250 mg of
CIS-3-(1-(6-chloropyridazin-4-yl)piperidin-4-yl)-1-(cyclopropylmethyl)-8--
(dimethylamino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one) as a light
brown solid. (TLC system: 10% MeOH in DCM; Rf: 0.35).
Step 2:
CIS-1-(cyclopropylmethyl)-8-(dimethylamino)-8-phenyl-3-(1-(pyridaz-
in-4-yl)piperidin-4-yl)-1,3-diazaspiro[4.5]decan-2-one
(SC_4096)
[0376] 10% Pd--C(125 mg) was added to a solution of
CIS-3-(1-(6-chloropyridazin-4-yl)piperidin-4-yl)-1-(cyclopropylmethyl)-8--
(dimethylamino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one) (0.25 g,
0.47 mmol) and triethylamine (96 mg, 0.95 mmol) in ethanol. The
resultant mixture was hydrogenated under balloon pressure for 4 h.
The reaction mixture was diluted with EtOH (10 mL); filtered
through a pad of celite and the filtrate was concentrated under
reduced pressure. The crude product was purified by flash
chromatography (silica gel 230-400 mesh, 5-10% methanol in DCM as
eluent) and further purified by reverse phase prep HPLC to afford
85 mg (17%) of
CIS-1-(cyclopropylmethyl)-8-(dimethylamino)-8-phenyl-3-(1-(pyridazin-4-yl-
)piperidin-4-yl)-1,3-diazaspiro[4.5]decan-2-one (SC_4096) as an
off-white solid. (TLC system: 10% MeOH in DCM; Rf: 0.35). Reverse
prep HPLC condition: column X-BRIDGE C.sub.18 (4.6.times.150 mm)
3.5 .mu.m; mobile phase:10 mM ammonium acetate in water
(A)/acetonitrile (B); gradient time(min)/% B: 0/5, 1.2/5, 3/55,
5/70, 7/95, 10/95, 12/100, 14/5, 16/5; flow rate: 1 ml/min;
diluent: (acetonitrile/water). .sup.1H NMR (DMSO): .delta. 8.92 (m,
1H), 8.55-8.54 (m, 1H), 7.34-7.30 (m, 4H), 7.24-7.21 (m, 1H),
6.91-6.89 (m, 1H), 4.09-4.07 (d, 2H), 3.84 (m, 1H), 3.09 (s, 2H),
2.95-2.90 (m, 4H), 2.62-2.59 (d, 2H), 2.12-2.09 (t, 2H), 1.96 (s,
6H), 1.60-1.56 (m, 4H), 1.42-1.39 (m, 2H), 1.31-1.28 (m, 2H), 0.91
(m, 1H), 0.46-0.43 (m, 2H), 0.26-0.23 (m, 2H). Mass: m/z 489.4
(M+H).sup.+.
Synthesis of SC_4091:
CIS-1-(cyclobutylmethyl)-8-(dimethylamino)-3-(2-methyl-2-(methylsulfonyl)-
propyl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one
##STR00126##
[0378] To a solution of
1-cyclobutylmethyl-8-dimethylamino-3-(2-methyl-2-methylsulfanyl-propyl)-8-
-phenyl-1,3-diaza-spiro[4.5]decan-2-one (45 mg, 0.1 mmol, 1.0 eq)
in THF/H.sub.2O (6 ml, 5:1) was added oxone (119 mg, 0.19 mmol, 1.9
eq.) at 0.degree. C. The reaction mixture was stirred at RT for 16
h, then quenched with sat. aq. NaHSO.sub.3, diluted with EtOAc (50
mL) and washed with sat. aq. NaHCO.sub.3 (25 ml). Organic layer was
dried over Na.sub.2SO.sub.4 and concentrated under reduced
pressure. The resulting crude product was purified by column
chromatography (neutral alumina; 1.5% MeOH in DCM) to yield
1-cyclobutylmethyl-8-dimethylamino-3-(2-methanesulfonyl-2-methyl-propyl)--
8-phenyl-1,3-diaza-spiro[4.5]decan-2-one (SC_4091) (100 mg, 0.17
mmol, 94%) as an off-white solid. .sup.1HNMR at 100.degree. C.
(DMSO-d6, 400 MHz), .delta. (ppm)=7.33-7.24 (m, 5H), 3.41 (s, 2H),
3.29 (s, 2H), 3.10 (d, 2H, J=7.04 Hz), 2.87 (s, 3H), 2.63-2.56 (m,
3H), 2.12-2.01 (m, 10H), 1.83-1.81 (m, 4H), 1.47-1.27 (m, 10H).
Mass: m/z 576.0 (M+H).sup.+.
Synthesis of SC_4098:
TRANS-8-(dimethylamino)-1-((1-hydroxycyclobutyl)methyl)-3-(2-(methylsulfo-
nyl)ethyl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one
##STR00127##
[0379] Step 1:
TRANS-8-(dimethylamino)-3-(2-(methylthio)ethyl)-8-phenyl-1,3-diazaspiro[4-
.5]decane-2,4-dione
[0380] In analogy to the method described for SC_4034
TRANS-8-(dimethylamino)-8-phenyl-1,3-diazaspiro[4.5]decane-2,4-dione
(step 1 of INT-1059) was reacted with
1-bromo-2-methylsulfanyl-ethane to be converted into
TRANS-8-(dimethylamino)-3-(2-(methylthio)ethyl)-8-phenyl-1,3-diazaspiro[4-
.5]decane-2,4-dione. Mass: m/z 362.2 (M+H).sup.+.
Step 2:
TRANS-8-(dimethylamino)-3-(2-(methylthio)ethyl)-8-phenyl-1,3-diaza-
spiro[4.5]decan-2-one
[0381] To a slurry of LiAlH.sub.4 (315 mg, 8.31 mmol, 6.0 eq.) in
THF (10 mL) was added a solution of
TRANS-8-dimethylamino-3-(2-methylsulfanyl-ethyl)-8-phenyl-1,3-diaza-spiro-
[4.5]decane-2,4-dione (500 mg, 1.38 mmol, 1.0 eq.) in THF (10 mL)
at 0.degree. C. under argon atmosphere and the reaction mixture was
stirred at reflux for 16 h. The reaction mixture was cooled to
0.degree. C. and quenched with sat. aq. Na.sub.2SO.sub.4 (10 mL).
The resulting suspension was stirred at RT for 30 min. The reaction
mixture was filtered through celite and filter cake was washed with
10% MeOH in DCM (30 mL). The combined filtrate was dried over
anhydr. Na.sub.2SO.sub.4 and concentrated under reduced pressure
and residue was dissolved in HCOOH (15 mL) and NaBH.sub.4 (314 mg,
8.31 mmol, 6.0 eq.) was added portionwise at 0.degree. C. The
reaction mixture was stirred at RT for 3 h, then basified with sat.
aq. NaHCO.sub.3 up to pH-8 and extracted with EtOAc (2.times.50
mL). Combined organic layer was washed with brine (30 mL), dried
over Na.sub.2SO.sub.4 and concentrated under reduced pressure to
get crude
TRANS-8-dimethylamino-3-(2-methylsulfanyl-ethyl)-8-phenyl-1,3-d-
iaza-spiro[4.5]decan-2-one (400 mg, 1.29 mmol, 83%) as a brown
solid which was used in the next step without further purification.
LC-MS: m/z [M+1].sup.+=348.4 (MW calc. 347.52).
Step 3:
TRANS-8-dimethylamino-1-(1-hydroxy-cyclobutylmethyl)-3-(2-methylsu-
lfanyl-ethyl)-8-phenyl-1,3-diaza-spiro[4.5]decan-2-one
[0382] To a solution of
TRANS-8-dimethylamino-3-(2-methylsulfanyl-ethyl)-8-phenyl-1,3-diaza-spiro-
[4.5]decan-2-one (450 mg, 1.29 mmol, 1.0 eq.) in DMSO (10 mL) was
added NaOH (363 mg, 9.07 mmol, 7.0 eq.) at RT. The reaction mixture
was heated to 60.degree. C. for 30 min, then cooled to RT and
1-oxa-spiro[2.3]hexane (435 mg, 5.18 mmol, 4.0 eq.) was added. The
reaction mixture was stirred at 60.degree. C. for 48 h, then
quenched with ice water (25 mL), extracted with EtOAc (2.times.50
mL). Combined organic layer was washed with brine (25 ml), dried
over Na.sub.2SO.sub.4, filtered and concentrated under reduced
pressure to get the crude product which was purified by column
chromatography (neutral alumina; 4% MeOH/DCM) to yield
TRANS-8-dimethylamino-1-(1-hydroxy-cyclobutylmethyl)-3-(2-methylsulfanyl--
ethyl)-8-phenyl-1,3-diaza-spiro[4.5]decan-2-one (120 mg, 0.27 mmol,
21%) as a brown liquid. LC-MS: m/z [M+1].sup.+=432.0 (MW calc.
431.64.
Step 4:
TRANS-8-(dimethylamino)-1-((1-hydroxycyclobutyl)methyl)-3-(2-(meth-
ylsulfonyl)ethyl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one
(SC_4098)
[0383] In analogy to the method described for step 2 of SC_4038
TRANS-8-dimethylamino-1-(1-hydroxy-cyclobutylmethyl)-3-(2-methylsulfanyl--
ethyl)-8-phenyl-1,3-diaza-spiro[4.5]decan-2-one was reacted with
oxone to be converted into
TRANS-8-(dimethylamino)-1-((1-hydroxycyclobutyl)methyl)-3-(2-(methylsulfo-
nyl)ethyl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one (SC_4098). Mass:
m/z 464.3 (M+H).sup.+. .sup.1HNMR (DMSO-d.sub.6, 400 MHz), .delta.
(ppm)=7.39-7.28 (m, 5H), 5.35 (s, 1H), 3.59-3.56 (m, 2H), 3.42-3.34
(m, 4H), 2.97-2.95 (m, 3H), 2.66 (s, 2H), 2.67 (bs, 2H), 2.59-2.56
(m, 2H), 2.00 (s, 6H), 1.77-0.163 (m, 6H), 1.50-1.27 (m, 5H),
1.05-0.98 (m, 1H).
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
##STR00128##
[0384] Step 1:
CIS-3-(8-(dimethylamino)-1-(methoxymethyl)-2-oxo-8-phenyl-1,3-diazaspiro[-
4.5]decan-3-yl)-2,2-dimethylpropanenitrile
[0385] 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
[0386] 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)
[0387] 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].sup.+=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).
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_4002
CIS-1-(Cyclobutyl-methyl)-8-dimethylamino-3-[2-[2-[2-[2- INT-987
19-bromo-2,5,8,11,14,17- SC_4003 620.4
[2-(2-methoxy-ethoxy)-ethoxy]-ethoxy]-ethoxy]-ethoxy]-
hexaoxanonadecane ethyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one
SC_4004 CIS-1-(Cyclobutyl-methyl)-8-dimethylamino-3-[2-[2-[2-[2-
INT-987 22-bromo-2,5,8,11,14,17,20- SC_4003 664.4
[2-[2-(2-methoxy-ethoxy)-ethoxy]-ethoxy]-ethoxy]-ethoxy]-
heptaoxadocosane
ethoxy]-ethyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one SC_4005
CIS-1-(Cyclobutyl-methyl)-8-dimethylamino-3-[2-[2-[2-[2- INT-987
16-bromo-2,5,8,11,14- SC_4003 576.4
(2-methoxy-ethoxy)-ethoxy]-ethoxy]-ethoxy]-ethyl]-8- pentaoxahexade
cane phenyl-1,3-diazaspiro[4.5]decan-2-one SC_4006
CIS-1-(Cyclobutyl-methyl)-8-dimethylamino-3-[2-(2- INT-987
1-bromo-2-(2- SC_4003 444.3
methoxy-ethoxy)-ethyl]-8-phenyl-1,3-diazaspiro[4.5]decan-
methoxyethoxy)ethane 2-one SC_4007
CIS-1-(Cyclobutyl-methyl)-8-dimethylamino-3-(2-methoxy- INT-987
1-bromo-2-methoxyethane SC_4003 400.3
ethyl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one SC_4008
CIS-1-(Cyclobutyl-methyl)-8-dimethylamino-3-[2-[2-[2-[2- INT-987
13-bromo-2,5,8,11- SC_4003 532.4
methoxy-ethoxy)-ethoxy]-ethoxy]-ethyl]-8-phenyl-1,3-
tetraoxatridecane diazaspiro[4.5]decan-2-one SC_4009
CIS-1-(Cyclobutyl-methyl)-8-dimethylamino-3-(2- INT-987 1-bromo-2-
SC_4025 448.3
methylsulfonyl-ethyl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-
(methylsulfonyl)ethane one SC_4011
CIS-8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]- INT-799
1-bromo-2- SC_4025 464.3 3-(2-methylsulfonyl-ethyl)-8-phenyl-1,3-
(methylsulfonyl)ethane diazaspiro[4.5]decan-2-one SC_4014
CIS-341-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8- INT-799
3-bromo-2,2- SC_4025 423.3
phenyl-1,3-diazaspiro[4.5]decan-3-yl]-2,2-dimethyl-
dimethylpropanenitrile propionitrile SC_4017
CIS-1-(Cyclobutyl-methyl)-8-dimethylamino-3-[2-[2-[2-[2- INT-987
25-bromo- SC_4003 708.5
[2-[2-[2-(2-methoxy-ethoxy)-ethoxy]-ethoxy]-ethoxy]-
2,5,8,11,14,17,20,23- ethoxy]-ethoxy]-ethoxy]-ethyl]-8-phenyl-1,3-
octaoxapentacosane diazaspiro[4.5]decan-2-one SC_4018
CIS-1-(Cyclobutyl-methyl)-8-dimethylamino-3-methyl-8- INT-987
Methyliodide SC_4025 356.3 phenyl-1,3-diazaspiro[4.5]decan-2-one
SC_4021 CIS-1-[(1-Hydroxy-cyclobutyl)-methyl]-8-methylamino-3-
SC_4011 -- SC_4010 450.2 (2-methylsulfonyl-ethyl)-8-phenyl-1,3-
diazaspiro[4.5]decan-2-one SC_4022
CIS-3-[1-[(1-Hydroxy-cyclobutyl)-methyl]-8-methylamino- SC_4029 --
SC_4010 397.3
2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-propionitrile SC_4024
CIS-241-[(1-Hydroxy-cyclobutyl)-methyl]-8-methylamino- SC_4030 --
SC_4010 383.2
2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-acetonitrile SC_4026
CIS-8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]- INT-799
4-(2-bromoethyl)morpholine SC_4025 471.3
3-(2-morpholin-4-yl-ethyl)-8-phenyl-1,3- diazaspiro[4.5]decan-2-one
SC_4029 CIS-3-[8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)- INT-799
3-bromopropanenitrile SC_4025 411.3
methyl]-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-
propionitrile SC_4030
CIS-2-[8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)- INT-799
2-bromoacetonitrile SC_4025 397.3
methyl]-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-
acetonitrile
TABLE-US-00004 in analogy m/z Example Chemical name Reactant I
Reactant II to method .sup.1H NMR data (M + H).sup.+ SC_4035
CIS-8-Dimethylamino-3- SC_4032 toluene-4-sulfonic SC_4034
.sup.1HNMR (DMSO-d6, 400 MHz), 450.1 (2-methylsulfonyl-ethyl)- acid
oxetan-3- .delta. (ppm) = 7.34-7.25 (m, 5H), 4.59
1-(oxetan-3-yl-methyl)-8- ylmethyl ester (t, 2H, 6.64 Hz) 4.35 (bs,
2H), phenyl-1,3- 3.48 (bs, 2H), 3.21 (s, 2H), 3.13
diazaspiro[4.5]decan-2- (bs, 1H), 2.95 (s, 3H), 2.67-2.65 one (m,
2H), 1.97 (s, 8H), 1.41-1.30 (m, 4H). SC_4036
CIS-8-Dimethylamino-1- SC_4032 1-bromo-3- SC_4034 .sup.1HNMR
(CDCl3, 400 MHz), .delta. 452.3 (3-methoxy-propyl)-3-(2-
methoxy-propane (ppm) = 7.35-7.25 (m, 5H, methylsulfonyl-ethyl)-8-
merged with CDCl3), 3.64 (t, 2H, phenyl-1,3- J = 6.32 Hz), 3.44 (t,
2H, J = 6.08 diazaspiro[4.5]decan-2- Hz), 3.34 (s, 3H), 3.28-3.19
m, one 6H), 2.95 (s, 3H), 2.64-2.61 (m, 2H), 2.22-2.16 (m, 2H),
2.01 (s, 6H), 1.89-1.86 (m, 2H), 1.29-1.27 (m, 4H). SC_4039
CIS-1-(Cyclobutyl- INT-987 1,6- SC_4027 .sup.1H NMR (DMSO-d6):
.delta. 7.37- 456.3 methyl)-8-dimethylamino- dioxaspiro[2.5]octane
7.31 (m, 4H), 7.26-7.23 (m, 1H), 3-[(4-hydroxy-tetrahydro- 4.52 (s,
1H), 3.60-3.56 (m, 4H), pyran-4-yl)-methyl]-8- 3.28 (s, 2H),
3.03-3.01 (m, 4H), phenyl-1,3- 2.68-2.65 (m, 2H), 2.49-2.46 (m,
diazaspiro[4.5]decan-2- 1H), 2.06-1.92 (m, 10H), 1.82- one 1.65 (m,
4H), 1.49-1.44 (m, 2H), 1.34-1.31 (m, 6H). SC_4040
CIS-1-(Cyclopropyl- INT-983 tetrahydro-2H- SC_4027 .sup.1H NMR
(DMSO-d6): .delta. 7.34- 412.3 methyl)-8-dimethylamino- pyran-4-yl
4- 7.25 (m, 5H), 3.86-3.84 (m, 2H), 8-phenyl-3-tetrahydro-
methylbenzenesulfonate 3.76-3.70 (m, 1H), 3.35 (m, 2H),
pyran-4-yl-1,3- 3.13 (s, 2H), 2.91 (d, 2H), 2.66-
diazaspiro[4.5]decan-2- 2.62 (m, 2H), 2.14 (t, 2H), 1.97 one (s,
6H), 1.66-1.58 (m, 2H), 1.46- 1.23 (m, 6H), 0.91 (m, 1H), 0.44 (m,
2H), 0.24 (m, 2H). SC_4041 CIS-1-(Cyclobutyl- INT-987 1-oxa-6-
SC_4027 .sup.1H NMR (DMSO-d6): .delta. 7.37- 504.3
methyl)-8-dimethylamino- thiaspiro[2.5]octane (for step 1), 7.23
(m, 5H), 5.02 (s, 1H), 3.27 3-[(4-hydroxy-1,1-dioxo- (step 1)
SC_4038 (s, 2H), 3.17-3.03 (m, 6H), 2.97- thian-4-yl)-methyl]-8-
(for step 2) 2.94 (m, 2H), 2.68-2.65 (m, 2H), phenyl-1,3- 2.54-2.46
(m, 1H), 2.07-1.92 (m, diazaspiro[4.5]decan-2- 10H), 1.87-1.84 (m,
4H), 1.80- one 1.66 (m, 4H), 1.34-1.31 (m, 4H). SC_4042
CIS-8-Dimethylamino-1- INT-799 tetrahydro-2H- SC_4027 .sup.1H NMR
(DMSO-d6): .delta. 7.37- 442.3 [(1-hydroxy-cyclobutyl)- pyran-4-yl
4- 7.23 (m, 5H), 6.05 (s, 1H), 3.87- methyl]-8-phenyl-3-
methylbenzenesulfonate 3.84 (m, 2H), 3.74-3.73 (m, 1H),
tetrahydro-pyran-4-yl-1,3- 3.36-3.35 (m, 2H), 3.24 (s, 2H),
diazaspiro[4.5]decan-2- 3.07 (s, 2H), 2.66-2.63 (m, 2H), one
2.06-1.83 (m, 12H), 1.65-1.58 (m, 3H), 1.48-1.32 (m, H), 7H).
SC_4043 CIS-1-[[8-Dimethylamino- SC_4032 toluene-4-sulfonic SC_4034
.sup.1HNMR (DMSO-d6, 400 MHz), 473.2 3-(2-methylsulfonyl- acid
1-cyano- .delta. (ppm) = 7.33-7.32 (m, 2H), 7.25
ethyl)-2-oxo-8-phenyl-1,3- cyclobutylmethyl ester (s, 3H),
3.69-3.66 (t, 2H, J = 5), diazaspiro[4.5]decan-1- 3.41 (s, 2H),
3.30-3.25 (m, 4H), yl]-methyl]-cyclobutane-1- 2.95 (s, 3H),
2.67-2.64 (d, 2H, J = carbonitrile 13.4), 2.45 (bs, 4H), 2.19-2.08
(m, 4H), 2.02 (s, 6H), 1.46-1.39 (m, 2H). SC_4045
CIS-8-Dimethylamino-1- INT-799 1-oxa-6- SC_4044 .sup.1 HNMR
(DMSO-d6): .delta. 7.37-7.25 520.3 [(1-hydroxy-cyclobutyl)-
thiaspiro[2.5]octane (for step 1), (m, 5H), 5.93 (s, 1H), 5.01 (s,
methyl]-3-[(4-hydroxy- (step 1) step 2 of 1H), 3.41 (s, 2H),
3.16-3.09 (m, 1,1-dioxo-thian-4-yl)- SC_4038 6H), 2.98-2.95 (m,
2H), 2.70- methyl]-8-phenyl-1,3- (for step 2) 2.66 (m, 2H),
2.06-2.03 (m, 4H), diazaspiro[4.5]decan-2- 1.97 (s, 6H), 1.89-1.87
(m, 6H), one 1.64-1.61 (m, 1H), 1.45-1.31 (m, 5H). SC_4046
CIS-1-(Cyclopropyl- INT-983 tetrahydro-2H- SC_4044 .sup.1H NMR
(DMSO-d6): .delta. 7.37- 460.3 methyl)-8-dimethylamino-
thiopyran-4-yl 4- (for step 1), 7.26 (m, 5H), 4.08-4.02 (m, 1H),
3-(1,1-dioxo-thian-4-yl)-8- methylbenzenesulfonate step 2 of
3.17-3.03 (m, 8H), 2.67-2.63 (m, phenyl-1,3- (step 1) SC_4038 2H),
2.32-2.04 (m, 12H), 1.46- diazaspiro[4.5]decan-2- (for step 2) 1.39
(m, 4H), 1.02-0.99 (m, 1H), one 0.54-0.50 (m, 2H), 0.34-0.30 (m,
2H). SC_4047 CIS-8-Dimethylamino-3- INT-799 tetrahydro-2H- SC_4044
.sup.1H NMR (DMSO-d6): .delta. 7.37- 490.3
(1,1-dioxo-thian-4-yl)-1- thiopyran-4-yl 4- (for step 1), 7.32 (m,
4H), 7.27-7.23 (m, 1H), [(1-hydroxy-cyclobutyl)-
methylbenzenesulfonate step 2 of 5.94 (s, 1H), 3.97-3.91 (m, 1H),
methyl]-8-phenyl-1,3- (step 1) SC_4038 3.33-3.31 (m, 2H), 3.27 (s,
2H), diazaspiro[4.5]decan-2- (for step 2) 3.07 (s, 2H), 3.02-2.99
(m, 2H), one 2.64-2.61 (m, 2H), 2.12-2.02 (m, 6H), 1.97 (s, 6H),
1.88-1.85 (m, 4H), 1.66-1.61 (m, 1H), 1.50-1.29 (m, 5H). SC_4049
CIS-3-(1-Benzoyl- SC_4054 benzoyl chloride SC_4048 .sup.1H NMR
(CDCl3): .delta. 7.40-7.34 515.4 piperidin-4-yl)-1- (m, 7H),
7.30-7.27 (m, 3H), 4.79 (cyclopropyl-methyl)-8- (m, 1H), 4.06-4.00
(m, 1H), 3.78 dimethylamino-8-phenyl- (br m, 1H), 3.90-3.05 (m,
5H), 1,3-diazaspiro[4.5]decan- 2.80-2.77 (br m, 1H), 2.65 (d, 2-one
2H), 2.27 (t, 2H), 2.05 (s, 6H), 1.82-1.62 (m, 3H), 1.46-1.41 (m,
5H), 1.04-0.99 (m, 1H), 0.53-0.50 (m, 2H), 0.33-0.30 (m, 2H).
SC_4050 CIS-l-(Cyclopropyl- SC_4054 isonicotinoyl chloride SC_4048
.sup.1H NMR (CDCl3): .delta. 8.67-8.66 516.3
methyl)-8-dimethylamino- hydrochloride (m, 2H), 7.36-7.35 (m, 2H),
7.30- 8-phenyl-3-[1-(pyridine-4- 7.27 (m, 3H), 7.25-7.24 (m, 2H),
carbonyl)-piperidin-4-yl]- 4.80-4.77 (m, 1H), 4.06-4.01 (m,
1,3-diazaspiro[4.5]decan- 1H), 3.65-3.62 (m, 1H), 3.14-3.05 2-one
(m, 5H), 2.82 (t, 1H), 2.67-2.65 (m, 2H), 2.28 (m, 2H), 2.05 (s,
6H), 1.86-1.84 (m, 1H), 1.71-1.62 (m, 2H), 1.46-1.39 (m, 5H), 1.03-
0.99 (m, 1H), 0.53-0.50 (m, 2H), 0.34-0.33 (m, 2H). SC_4051
CIS-1-(Cyclopropyl- INT-983 1,6- SC_4044 .sup.1H NMR (DMSO-d6):
.delta. 7.37- 442.3 methyl)-8-dimethylamino- dioxaspiro[2.5]octane
7.33 (m, 4H), 7.27-7.23 (m, 1H), 3-[(4-hydroxy-tetrahydro- 4.54 (s,
1H), 3.60-3.53 (m, 4H), pyran-4-yl)-methyl]-8- 3.32 (m, 2H), 3.03
(s, 2H), 2.91 phenyl-1,3- (d, 2H), 2.67 (d, 2H), 2.15 (t, 2H),
diazaspiro[4.5]decan-2- 1.97 (s, 6H), 1.49-1.44 (m, 2H), one
1.40-1.31 (m, 6H), 0.95-0.90 (m, 1H), 0.46-0.43 (m, 2H), 0.30-0.21
(m, 2H). SC_4053 CIS-3-[(1-Acetyl- SC_4058 acetyl chloride SC_4048
.sup.1H NMR (DMSO d6): .delta. 7.35-7.34 467.3
piperidin-4-yl)-methyl]-1- (m, 4H), 7.25 (m, 1H), 4.31-4.28
(cyclopropyl-methyl)-8- (m, 1H), 3.77-3.74 (m, 1H), 3.15
dimethylamino-8-phenyl- (s, 2H), 2.97-2.90 (m, 5H), 2.68-
1,3-diazaspiro[4.5]decan- 2.64 (m, 2H), 2.19-2.13 (m, 2H), 2-one
1.97-1.95 (m, 9H), 1.76 (m, 1H), 1.59-1.52 (m, 2H), 1.43-1.31 (m,
4H), 1.03-0.87 (m, 3H), 0.45-0.44 (m, 2H), 0.25-0.24 (m, 2H).
SC_4058 CIS-1-(Cyclopropyl- INT-983 tert-butyl 4- SC_4034 .sup.1H
NMR (DMSO d6): .delta. 7.37-7.34 425.3 methyl)-8-dimethylamino-
((tosyloxy)methyl) (for step 1), (m, 4H), 7.27-7.23 (m, 1H), 3.13
8-phenyl-3-(piperidin-4- piperidine- step 2 of (s, 2H), 2.91-2.87
(m, 6H), 2.67- yl-methyl)-1,3- 1-carboxylate SC_4054 2.64 (m, 2H),
2.39-2.33 (m, 2H), diazaspiro[4.5]decan-2- (step 1) (for step 2)
2.18-2.12 (m, 2H), 1.97 (s, 6H), one 1.58-1.54 (m, 1H), 1.47-1.30
(m, 6H), 0.98-0.88 (m, 3H), 0.46-0.42 (m, 2H), 0.26-0.22 (m, 2H).
SC_4059 CIS-3-(1-Benzoyl- INT-976 tert-butyl 4-(tosyloxy) SC_4054
.sup.1H NMR (DMSO d6): .delta. 7.42-7.23 461.3 piperidin-4-yl)-8-
piperidine-1- (for steps (m, 10H), 6.67 (brs, 1H), 4.51 (m,
dimethylamino-8-phenyl- carboxylate (step 1), 1, 2), (1H), 3.75 (m,
1H), 3.54 (m, 1H), 1,3-diazaspiro[4.5]decan- benzoyl chloride
SC_4048 3.05 (s, 3H), 2.75 (m, 1H), 2.34 2-one (step 3) (for step
3) (m, 2H), 1.93 (s, 6H), 1.77 (m, 4H), 1.55-1.35 (m, 6H). SC_4060
CIS-8-Dimethylamino-8- INT-976 isonicotinoyl chloride SC_4054
.sup.1H NMR (DMSO d6): .delta. 8.64-8.62 462.3
phenyl-3-[1-(pyridine-4- hydrochloride (for steps (m, 2H),
7.37-7.32 (m, 6H), 7.26- carbonyl)-piperidin-4-yl]- 1, 2), 7.23 (m,
1H), 6.67 (br s, 1H), 1,3-diazaspiro[4.5]decan- SC_4048 4.50 (d,
1H), 3.80-3.73 (m, 1H), 2-one (for step 3) 3.40-3.37 (m, 1H),
3.11-3.05 (m, 3H), 2.78 (t, 1H), 2.36-2.33 (m, 2H), 1.93 (s, 6H),
1.80-1.65 (m, 4H), 1.61-1.52 (m, 3H), 1.49-1.35 (m, 3H). SC_4061
CIS-3-(1-Acetyl-piperidin- INT-976 acetyl chloride SC_4054 .sup.1H
NMR (DMSO-d6): .delta. 7.36- 399.3 4-yl)-8-dimethylamino-8- (for
steps 7.23 (m, 5H), 6.68 (br, s, 1H), phenyl-1,3- 1, 2), 4.40 (d,
1H), 3.80 (d, 1H), 3.69 diazaspiro[4.5]decan-2- SC_4048 (m, 1H),
3.05-2.99 (m, 3H), 2.32 one (for step 3) (m, 3H), 1.95-1.92 (m,
9H), 1.78- 1.76 (m, 4H), 1.50-1.46 (m, 3H), 1.33-1.30 (m, 3H).
SC_4062 CIS-1-(Cyclopropyl- INT-983 1-oxa-6- SC_4044 .sup.1H NMR
(DMSO-d6): .delta. 7.37- 490.3 methyl)-8-dimethylamino-
thiaspiro[2.5]octane (for step 1), 7.33 (m, 4H), 7.27-7.24 (m, 1H),
3-[(4-hydroxy-1,1-dioxo- (step 1) step 2 of 5.04 (s, 1H), 3.30 (m,
2H), 3.15- thian-4-yl)-methyl]-8- SC_4038 3.07 (m, 4H), 2.97-2.92
(m, 4H), phenyl-1,3- (for step 2) 2.69-2.66 (m, 2H), 2.18-2.13 (m,
diazaspiro[4.5]decan-2- 2H), 1.97 (s, 6H), 1.87-1.84 (m, one 4H),
1.38-1.31 (m, 4H), 0.94-0.91 (m, 1H), 0.47-0.43 (m, 2H), 0.26- 0.24
(m, 2H). SC_4063 CIS-8-Dimethylamino-1- INT-799 tert-butyl
bromoacetate SC_4055 .sup.1H NMR (DMSO d6): .delta. 7.37-7.33 430.3
[(1-hydroxy-cyclobutyl)- (step 1), (m, 4H), 7.26-7.23 (m, 1H), 6.11
methyl]-3-(2-hydroxy-2- methylmagnesium (s, 1H), 4.41 (s, 1H), 3.42
(s, 2H), methyl-propyl)-8-phenyl- bromide (step 3) 3.09 (s, 2H),
2.98 (s, 2H), 2.70- 1,3-diazaspiro[4.5]decan- 2.67 (m, 2H),
2.07-2.02 (m, 4H), 2-one 1.97 (s, 6H), 1.91-1.83 (m, 3H), 1.63-1.61
(m, 1H), 1.45-1.42 (m, 2H), 1.36-1.32 (m, 3H), 1.04 (s, 6H).
SC_4066 CIS-8-Dimethylamino- INT-976 1-bromo-2- SC_4003 1H NMR (600
MHz, DMSO) .delta. 380.2 1,3-bis(2-methylsulfonyl-
methylsulfonyl-ethane 7.40-7.32 (m, 4H), 7.30-7.23 (m,
ethyl)-8-phenyl-1,3- 1H), 3.52 (t, 2H), 3.46-3.31 (m,
diazaspiro[4.5]decan-2- 1H), 3.27 (s, 2H), 3.05 (s, 3H), one 2.97
(s, 3H), 2.72-2.63 (m, 2H), 2.11-2.01 (m, 2H), 1.99 (s, 6H),
1.45-1.36 (m, 4H). SC_4067 CIS-N-[1-[[1- SC_4064 acetyl chloride
SC_4048 [0375] 1HNMR (DMSO-d6, 400 439.1 (Cyclopropyl-methyl)-8-
MHz), .delta. (ppm) = 7.98 (s, 1H), dimethylamino-2-oxo-8-
7.36-7.25 (m, 5H), 3.25 (s, 2H), phenyl-1,3- (3.12 (s, 2H), 2.89
(d, 2H, J = diazaspiro[4.5]decan-3- 6.48 Hz), 2.67-2.64 (m, 2H),
yl]-methyl]-cyclopropyl]- 2.16-2.07 (m, 2H), 1.97 (s, 6H),
acetamide 1.67 (s, 3H), 1.44-1.36 (m, 4H), 0.91 (bs, 1H), 0.62-0.42
(m, 6H), 0.25-0.23 (m, 2H). SC_4068 CIS-1-(Cyclopropyl- SC_4058
5-bromo-2- SC_4056 1H NMR (DMSO d6): .delta. 8.52 (s, 503.4
methyl)-8-dimethylamino- (trifluoromethyl) 1H), 8.45 (s, 2H),
7.37-7.33 (m, 8-phenyl-3-[(1-pyrimidin- pyrimidine 4H), 7.27-7.23
(m, 1H), 3.83-3.80 5-yl-piperidin-4-yl)- (m, 2H), 3.17 (s, 2H),
2.96-2.75 methyl-1,3- (m, 4H), 2.73-2.65 (m, 4H), 2.16
diazaspiro[4.5]decan-2- (m, 2H), 1.98 (s, 6H), 1.65 (m,
one 1H), 1.65-1.63 (m, 2H), 1.40-1.32 (m, 4H), 1.20-1.17 (m, 2H),
0.94 (m, 1H), 0.46-0.44 (m, 2H), 0.26- 0.24 (m, 2H). SC_4069
CIS-8-Dimethylamino-8- INT-1051 5-bromopyrimidine SC_4056 1H NMR
(DMSO d6): .delta. 8.52 (s, 449.3 phenyl-3-[(1-pyrimidin-5- 1H),
8.45 (s, 2H), 7.37-7.33 (m, yl-piperidin-4-yl)-methyl]- 4H),
7.26-7.23 (m, 1H), 6.72 1,3-diazaspiro[4.5]decan- (broad s, 1H),
3.82-3.79 (m, 2H), 2-one 3.18 (s, 2H), 2.90-2.89 (m, 2H), 2.72-2.69
(m, 2H), 2.30 (m, 2H), 1.92 (s, 6H), 1.79-1.69 (m, 5H), 1.64-1.61
(m, 2H), 1.35 (m, 2H), 1.20-1.12 (m, 2H). SC_4070
CIS-8-Dimethylamino-8- INT-1050 5-bromopyrimidine SC_4056 1H NMR
(DMSO-d6): .delta. 8.52 (s, 435.3 phenyl-3-(1-pyrimidin-5- 1H),
8.46 (s, 2H), 7.36-7.30 (m, yl-piperidin-4-yl)-1,3- 4H), 7.24-7.22
(m, 1H), 6.71 (br diazaspiro[4.5]decan-2- s, 1H), 3.90-3.88 (m,
2H), 3.71- one 3.67 (m, 1H), 3.00 (s, 2H), 2.84- 2.79 (m, 2H), 2.28
(br s, 2H), 1.92 (s, 6H), 1.78 (br m, 4H), 1.66-1.55 (m, 4H),
1.34-1.33 (m, 2H). SC_4072 CIS-1-(Cyclopropyl- INT-1052
4-chlorobutanoyl SC_4048 1H NMR (DMSO-d6): .delta. 7.37- 467.3
methyl)-8-dimethylamino- chloride (step 1) (step 1), 7.32 (m, 4H),
7.27-7.24 (m, 1H), 3-[2-methyl-2-(2-oxo- procedure 3.40-3.36 (m,
4H), 3.16 (s, 2H), pyrrolidin-1-yl)-propyl]-8- described 2.92 (d,
2H), 2.69-2.66 (m, 2H), phenyl-1,3- (step 2) 2.19-2.07 (m, 4H),
1.97 (s, 6H), diazaspiro[4.5]decan-2- 1.79-1.75 (m, 2H), 1.37-1.29
(m, one 4H), 1.26 (s, 6H), 0.93-0.92 (m, 1H), 0.47-0.42 (m, 2H),
0.27-0.24 (m, 2H). SC_4073 CIS-1-(Cyclopropyl- INT-1052
3-chloropropane-1- SC_4072 1H NMR (DMSO-d6): .delta. 7.37- 503.3
methyl)-8-dimethylamino- sulfonyl chloride 7.32 (m, 4H), 7.27-7.24
(m, 1H), 3-[2-(1,1-dioxo- (step 1) 3.34-3.27 (m, 4H), 3.16-3.13 (m,
[1,2]thiazolidin-2-yl)-2- 4H), 2.93 (d, 2H), 2.67-2.64 (m,
methyl-propyl]-8-phenyl- 2H), 2.16-2.05 (m, 4H), 1.97 (s,
1,3-diazaspiro[4.5]decan- 6H), 1.40-1.36 (m, 4H), 1.29 (s, 2-one
6H), 0.93-0.92 (m, 1H), 0.46-0.44 (m, 2H), 0.26-0.24 (m, 2H).
SC_4074 CIS-8-Dimethylamino-1- INT-799 2-(4-(benzyloxy) SC_4052 1H
NMR (DMSO-d6): .delta. 7.37- 486.4 [(1-hydroxy-cyclobutyl)-
tetrahydro-2H-pyran- 7.34 (m, 4H), 7.27-7.24 (m, 1H),
methyl]-3-[2-(4-hydroxy- 4-yl)ethyl 4- 6.17 (s, 1H), 4.28 (br s,
1H), 3.61- tetrahydro-pyran-4-yl)- methylbenzenesulfonate 3.51 (m,
4H), 3.25 (s, 2H), 3.22- ethyl]-8-phenyl-1,3- 3.18 (m, 2H), 3.07
(s, 2H), 2.68- diazaspiro[4.5]decan-2- 2.65 (m, 2H), 2.06-2.03 (m,
4H) one 1.97 (s, 6H), 1.91-1.83 (m, 2H), 1.64-1.61 (m, 1H),
1.57-1.50 (m, 2H), 1.47-1.29 (m, 9H). SC_4075 CIS-1-(Cyclobutyl-
INT-987 4-allyl-4- SC_4071 1H NMR (DMSO-d6): .delta. 7.37- 518.3
methyl)-8-dimethylamino- (benzyloxy)tetrahydro- 7.23 (m, 5H), 4.76
(s, 1H), 3.16- 3-[2-(4-hydroxy-1,1-dioxo- 2H-thiopyran 3.10 (m,
6H), 3.01 (d, 2H), 2.91- thian-4-yl)-ethyl]-8- 2.88 (m, 2H),
2.67-2.63 (m, 2H), phenyl-1,3- 2.02-1.82 (m, 14H), 1.80-1.65 (m,
diazaspiro[4.5]decan-2- 5H), 1.58 (m, 2H), 1.42-1.35 (m, one 2H),
1.28-1.26 (m, 2H). SC_4076 CIS-3-[(1-Acetyl- INT-1051 acetyl
chloride SC_4048 1H NMR (DMSO d6): .delta. 7.37- 413.3
piperidin-4-yl)-methyl]-8- 7.23 (m, 5H), 6.72 (b s, 1H),
dimethylamino-8-phenyl- 4.30-4.27 (m, 1H), 3.76-3.73 (m,
1,3-diazaspiro[4.5]decan- 1H), 3.03 (s, 2H), 2.96-2.91 (m, 2-one
1H), 2.86-2.81 (m, 2H), 2.44 (m, 1H), 2.32 (m, 2H), 1.95-1.92 (m,
9H), 1.79-1.68 (m, 5H), 1.58-1.50 (m, 2H), 1.36-1.34 (m, 2H), 1.05-
1.01 (m, 1H), 0.98-0.92 (m, 1H). SC_4077 CIS-8-Dimethylamino-3-
SC_4032 2-chloro-1-pyrrolidin- SC_4003 1H NMR (600 MHz, DMSO)
.delta. 491.3 (2-methylsulfonyl-ethyl)- 1-yl-ethanone 7.38-7.30 (m,
4H), 7.29-7.22 (m, 1-(2-oxo-2-pyrrolidin-1- 1H), 3.79 (s, 2H),
3.53-3.48 (m, yl-ethyl)-8-phenyl-1,3- 5H), 3.35-3.27 (m, 5H), 2.96
(s, diazaspiro[4.5]decan-2- 3H), 2.67-2.59 (m, 2H), 1.98-1.87 one
(m, 10H), 1.77 (p, 2H), 1.44-1.34 (m, 4H). SC_4078 TRANS-8-
INT-1059 1-bromo-2- SC_4003 1HNMR (DMSO-d6, 400 MHz at 380.2
Dimethylamino-3-(2- methylsulfonyl-ethane 100.degree. C.), .delta.
(ppm) = 7.35-7.24 methylsulfonyl-ethyl)-8- (m, 5H), 6.43 (s, 1H),
3.50 (t, 2H, phenyl-1,3- J = 6.46 Hz), 3.31-3.22 (m, 4H),
diazaspiro[4.5]decan-2- 2.95 (3H, merged with DMSO- one water),
2.17 (bs, 2H), 1.99 (bs, 8H), 1.72 (bs, 2H), 1.45-1.39 (m, 2H).
SC_4079 CIS-8-Dimethylamino-1- INT-799 4-allyl-4- SC_4071 1H NMR
(DMSO-d6): .delta. 7.37- 534.3 [(1-hydroxy-cyclobutyl)-
(benzyloxy)tetrahydro- 7.33 (m, 4H), 7.27-7.24 (m, 1H),
methyl]-3-[2-(4-hydroxy- 2H-thiopyran 6.13 (br s, 1H), 3.26 (s,
2H), 3.20- 1,1-dioxo-thian-4-yl)- 3.11 (m, 4H), 3.07 (s, 2H), 2.92-
ethyl]-8-phenyl-1,3- 2.89 (m, 2H), 2.68-2.65 (m, 2H),
diazaspiro[4.5]decan-2- 2.05-2.01 (m, 4H), 1.97 (s, 6H), one
1.89-1.85 (m, 8H), 1.64-1.60 (m, 3H), 1.43-1.32 (m, 4H). SC_4081
CIS-N-[2-[1- INT-1052 acetyl chloride SC_4048 1HNMR (CDCl3, 400
MHz), .delta. 441.3 (Cyclopropyl-methyl)-8- (ppm) = 7.53 (s, 1H),
7.36-7.28 dimethylamino-2-oxo-8- (m, 5H), 3.28 (s, 2H), 3.08-3.04
phenyl-1,3- (m, 4H), 2.66-2.63 (m, 2H), 2.31-
diazaspiro[4.5]decan-3- 2.25 (m, 2H), 2.03 (s, 6H), 1.87
yl]-1,1-dimethyl-ethyl]- (s, 3H), 1.51-1.41 (m, 4H), 1.35 acetamide
(s, 6H), 1.02 (bs, 1H), 0.53-0.51 (m, 2H), 0.33-0.32 (m, 2H).
SC_4082 CIS-N-[2-[1- INT-1052 methanesulfonyl SC_4048 1HNMR (CDCl3,
400 MHz), .delta. 477.2 (Cyclopropyl-methyl)-8- chloride (ppm) =
7.34-7.25 (m, 5H), 6.16 dimethylamino-2-oxo-8- (s, 1H), 3.31 (s,
2H), 3.10-3.05 phenyl-1,3- (m, 4H), 2.97 (s, 3H), 2.67-2.63
diazaspiro[4.5]decan-3- (m, 2H), 2.32-2.25 (m, 2H), 2.03
yl]-1,1-dimethyl-ethyl]- (s, 6H), 1.51-1.43 (m, 4H), 1.37
methanesulfonic acid (s, 6H), 1.01-0.99 (m, 1H), 0.52- amide 0.50
(m, 2H), 0.32 (m, 2H). SC_4083 CIS-8-Dimethylamino-1- INT-799
3-(benzyloxy)-3- SC_4071 1H NMR (DMSO-d6): .delta. 7.36- 458.3
[(1-hydroxy-cyclobutyl)- vinyloxetane 7.33 (m, 4H), 7.26-7.25 (m,
1H), methyl]-3-[2-(3-hydroxy- 6.12 (s, 1H), 5.65 (s, 1H), 4.39 (d,
oxetan-3-yl)-ethyl]-8- 2H), 4.33 (d, 2H), 3.29 (s, 2H), phenyl-1,3-
3.17-3.14 (m, 2H), 3.08 (s, 2H), diazaspiro[4.5]decan-2- 2.68-2.65
(m, 2H), 2.07-2.02 (m, one 4H), 1.97 (s, 6H), 1.91-1.86 (m, 4H),
1.69-1.59 (m, 1H), 1.43-1.40 (m, 4H), 1.38-1.31 (m, 1H). SC_4085
CIS-N-[2-[8- INT-1053 acetyl chloride SC_4048 1HNMR (DMSO-d6, 400
MHz), 471.3 Dimethylamino-1-[(1- .delta. (ppm) = 7.48 (s, 1H), 7.32
(m, hydroxy-cyclobutyl)- 5H), 5.95 (s, 1H), 3.29-3.26 (m,
methyl]-2-oxo-8-phenyl- 4H), 3.06 (s, 2H), 2.65-2.62 (m,
1,3-diazaspiro[4.5]decan- 2H), 2.05-1.99 (m, 4H), 1.93 (s,
3-yl]-1,1-dimethyl-ethyl]- 6H), 1.85-1.82 (m, 2H), 1.67 (s,
acetamide 3H), 1.60-1.59 (m, 1H), 1.43-1.26 (m, 5H), 1.13 (m, 6H).
SC_4086 CIS-N-[2-[8- INT-1053 methanesulfonyl SC_4048 1HNMR
(DMSO-d6, 400 MHz), 507.1 Dimethylamino-1-[(1- chloride .delta.
(ppm) = 7.35-7.25 (m, 5H), 6.90 hydroxy-cyclobutyl)- (s, 1H), 5.95
(s, 1H), 3.44 (s, 2H), methyl]-2-oxo-8-phenyl- 3.14 (s, 2H), 3.10
(s, 2H), 2.92 (s, 1,3-diazaspiro[4.5]decan- 3H), 2.68-2.66 (m, 3H),
2.08-2.03 3-yl]-1,1-dimethyl-ethyl]- (m, 4H), 1.97 (s, 6H),
1.88-1.85 methanesulfonic acid (m, 2H), 1.47-1.31 (m, 7H), 1.21
amide (s, 6H). SC_4087 CIS-1-(Cyclopropyl- SC_4054 3-bromopyridine
SC_4056 1H NMR (DMSO d6): .delta. 8.26 (d, 488.4
methyl)-8-dimethylamino- 1H), 7.93 (m, 1H), 7.35-7.27 (m,
8-phenyl-3-(1-pyridin-3- 4H), 7.25-7.23 (m, 2H), 7.17-7.15
yl-piperidin-4-yl)-1,3- (m, 1H), 3.80 (d, 2H), 3.77-3.68
diazaspiro[4.5]decan-2- (m, 1H), 3.29-3.27 (m, 1H), 3.13 one (s,
2H), 2.91 (d, 2H), 2.77 (t, 2H), 2.64-2.62 (m, 1H), 2.14 (t, 2H),
1.97 (s, 6H), 1.72-1.68 (m, 2H), 1.61-1.59 (m, 2H), 1.44 (t, 2H),
1.32 (d, 2H), 0.94-0.90 (m, 1H), 0.47-0.44 (m, 2H), 0.28-0.25 (m,
2H). SC_4088 CIS-1-(Cyclopropyl- INT-1063 1-bromo-2- SC_4032 1H NMR
(600 MHz, DMSO) .delta. 452.2 methyl)-8-dimethylamino-
methylsulfonyl-ethane 7.44-7.36 (m, 1H), 7.18 (d, 1H),
8-(3-fluorophenyl)-3-(2- 7.15 (dt, 1H), 7.10 (td, 1H), 3.51
methylsulfonyl-ethyl)-1,3- (t, 2H), 3.32 (t, 2H), 3.23 (s, 2H),
diazaspiro[4.5]decan-2- 2.96 (s, 3H), 2.93 (d, 2H), 2.68- one 2.60
(m, 2H), 2.18-2.10 (m, 2H), 2.00 (s, 6H), 1.45-1.33 (m, 4H), 0.93
(tdd, 1H), 0.50-0.41 (m, 2H), 0.31-0.22 (m, 2H). SC_4089
CIS-1-(Cyclopropyl- SC_4054 4-bromopyridine SC_4056 1H NMR (DMSO
d6): .delta. 8.09- 488.4 methyl)-8-dimethylamino- 8.08 (d, 2H),
7.33-7.30 (m, 4H), 8-phenyl-3-(1-pyridin-4-yl- 7.24-7.23 (m, 1H),
6.77-76 (d, piperidin-4-yl)-1,3- 2H), 3.98-3.96 (d, 2H), 3.80 (m,
diazaspiro[4.5]decan-2- 1H), 3.09 (s, 2H), 2.91-2.84 (m, one 4H),
2.62-2.59 (m, 2H), 2.15-2.10 (m, 2H), 1.94 (m, 6H), 1.59-1.56 (m,
4H), 1.42-1.37 (m, 2H), 1.33- 1.29 (m, 2H), 0.91-0.90 (m, 1H),
0.46-0.43 (m, 2H), 0.26 (m, 2H). SC_4090 CIS-8-Dimethylamino-1-
INT-1053 4-chlorobutanoyl SC_4072 1H NMR (DMSO-d6): .delta. 7.37-
497.4 [(1-hydroxy-cyclobutyl)- chloride (step 1) 7.32 (m, 4H),
7.27-7.25 (m, 1H), methyl]-3-[2-methyl-2-(2- 6.03 (s, 1H), 3.43 (s,
2H), 3.39 (t, oxo-pyrrolidin-1-yl)- 2H), 3.27 (s, 2H), 2.09 (s,
2H), propyl]-8-phenyl-1,3- 2.69-2.66 (m, 2H), 2.12 (t, 2H),
diazaspiro[4.5]decan-2- 2.07-2.03 (m, 4H), 1.96 (s, 6H), one
1.90-1.86 (m, 2H), 1.84-1.76 (m, 2H), 1.63-1.61 (m, 1H), 1.45-1.43
(m, 2H), 1.41 (m, 3H), 1.35-1.31 (m, 6H). SC_4092
TRANS-1-(Cyclobutyl- INT-1056 -- SC_4091 1HNMR (DMSO-d6, 400 MHz),
476.3 methyl)-8-dimethylamino- .delta. (ppm) = 7.44-7.29 (m, 5H),
3.38 3-(2-methyl-2- (s, 2H), 3.34 (s, 2H), 2.94 (s, 3H),
methylsulfonyl-propyl)-8- 2.87 (s, 3H), 2.64 (d, 2H, J =
phenyl-1,3- 12.24 Hz), 2.60 (d, 2H, J = 7.24
diazaspiro[4.5]decan-2- Hz), 2.10-2.06 (m, 1H), 1.90 (s, one 6H),
1.73-1.49 (m, 6H), 1.42-1.33 (m, 6H), 1.27 (s, 6H). SC_4093
CIS-8-Dimethylamino-3- INT-799 3-chloropropane-1- SC_4072 1H NMR
(DMSO-d6): .delta. 7.37- 533.3 [2-(1,1-dioxo- sulfonyl chloride
7.32 (m, 4H), 7.27-7.23 (m, 1H), [1,2]thiazolidin-2-yl)-2- (step 1)
6.01 (s, 1H), 3.42 (s, 2H), 3.36- methyl-propyl]-1-[(1- 3.31 (m,
2H), 3.18-3.13 (m, 4H), hydroxy-cyclobutyl)- 3.10 (s, 2H),
2.68-2.64 (m, 2H), methyl]-8-phenyl-1,3- 2.10-2.03 (m, 6H), 1.96
(s, 6H), diazaspiro[4.5]decan-2- 1.90-1.84 (m, 2H), 1.70-1.60 (m,
one 1H), 1.47-1.44 (m, 2H), 1.41-1.35 (m, 3H), 1.32 (s, 6H).
SC_4094 CIS-1-(Cyclopropyl- INT-1063 1,6- SC_4044 1H NMR (DMSO-d6):
.delta. 7.34- 460.3 methyl)-8-dimethylamino- dioxaspiro[2.5]octane
7.29 (m, 1H), 7.06-7.04 (m, 1H), 8-(3-fluorophenyl)-3-[(4-
6.99-6.95 (m, 2H), 4.43 (s, 1H), hydroxy-tetrahydro-pyran-
3.82-3.78 (m, 2H), 3.74-3.71 (m, 4-yl)-methyl]-1,3- 2H), 3.28 (s,
2H), 3.14 (s, 2H), diazaspiro[4.5]decan-2- 3.06 (d, 2H), 2.59 (d,
2H), 2.26 (t, one 2H), 2.05 (s, 6H), 1.58-1.49 (m, 4H), 1.47-1.42
(m, 4H), 1.02 (m, 1H), 0.54-0.51 (m, 2H), 0.33-031 (m, 2H) SC_4095
CIS-8-Dimethylamino-1- INT-1072 5-bromopyrimidine SC_4056 519.3
[(1-hydroxy-cyclobutyl)- methyl]-8-phenyl-3-(1-
pyrimidin-5-yl-piperidin- 4-yl)-1,3- diazaspiro[4.5]decan-2- one
SC_4097 CIS-2-[8-Dimethylamino- SC_4032 2-chloro-N,N- SC_4003 1H
NMR (600 MHz, DMSO) .delta. 465.3 3-(2-methylsulfonyl-
dimethyl-acetamide 7.35 (d, 4H), 7.29-7.22 (m, 1H),
ethyl)-2-oxo-8-phenyl-1,3- 3.86 (s, 2H), 3.51 (t, 2H), 3.32 (t,
diazaspiro[4.5]dccan-1- 2H), 3.29 (s, 2H), 3.03 (s, 3H),
yl]-N,N-dimethyl- 2.97 (s, 3H), 2.84 (s, 3H), 2.64 (d, acetamide
2H), 2.02-1.86 (m, 8H), 1.44-1.35 (m, 4H).
SC_4099 CIS-1-(Cyclopropyl- INT-1073 5-bromopyrimidine SC_4056
507.3 methyl)-8-dimethylamino- 8-(3-fluorophenyl)-3-(1-
pyrimidin-5-yl-piperidin- 4-yl)-1,3- diazaspiro[4.5]decan-2- one
SC_4100 CIS-1- SC_4088 SC_4010 438.2 (cyclopropylmethyl)-8-(3-
fluorophenyl)-8- (methylamino)-3-(2- (methylsulfonyl)ethyl)-
1,3-diazaspiro[4.5]decan- 2-one SC_4101 CIS-1- INT-983
1-oxaspiro[2.3]hexane SC_4044 (cyclopropylmethyl)-8-
(dimethylamino)-3-((1- hydroxycyclobutyl) methyl)-8-phenyl-1,3-
diazaspiro[4.5]decan-2- one SC_4102 CIS-8-(dimethylamino)-8-
(3-fluorophenyl)-3-((4- INT-1074 1-oxa-6- SC_4044 hydroxy-1,1-
thiaspiro[2.5]octane (for step 1), dioxidotetrahydro-2H- (step 1)
step 2 of thiopyran-4-yl)methyl)-1- SC_4038 ((1-hydroxycyclobutyl)
(for step 2) methyl)-1,3- diazaspiro[4.5]decan-2- one SC_4103
CIS-8-(dimethylamino)-8- (3-fluorophenyl)-1-((1- hydroxycyclobutyl)
INT-1074 1,6- SC_4044 methyl)-3-((4- dioxaspiro[2.5]octane
hydroxytetrahydro-2H- pyran-4-yl)methyl)-1,3-
diazaspiro[4.5]decan-2- one SC_4104 CIS-1- INT-1063 1-oxa-6-
SC_4044 (cyclopropylmethyl)-8- thiaspiro[2.5]octane (for step 1),
(dimethylamino)-8-(3- (step 1) step 2 of fluorophenyl)-3-((4-
SC_4038 hydroxy-1,1- (for step 2) dioxidotetrahydro-2H-
thiopyran-4-yl)methyl)- 1,3-diazaspiro[4.5]decan- 2-one SC_4105
CIS-1- INT-983 3-(bromomethyl) SC_4032 (cyclopropylmethyl)-8-
oxetane (dimethylamino)-3- (oxetan-3-ylmethyl)-8- phenyl-1,3-
diazaspiro[4.5]decan-2- one SC_4106 CIS-8-(dimethylamino)-8-
INT-976 (R)-1-(thiophen-3-yl) SC_4032 398.2
phenyl-3-((S)-1-(thiophen- propan-2- 3-yl)propan-2-yl)-1,3-
ylmethanesulfonate diazaspiro[4.5]decan-2- one SC_4107
CIS-8-(dimethylamino)-8- INT-976 (1-(trifluoromenthyl) SC_4032
phenyl-1,3-bis((1- cyclopropyl)methyl 4- (trifluoromethyl)
methylbenzenesulfonate cyclopropyl)methyl)-1,3-
diazaspiro[4.5]decan-2- one SC_4108 CIS-8-(dimethylamino)- INT-976
(1-fluorocyclopropyl) SC_4032 1,3-bis((1- methyl 4-
fluorocyclopropyl) methylbenzenesulfonate methyl)-8-phenyl-1,3-
diazaspiro[4.5]decan-2- one SC_4109 CIS-1- INT-983 (3-(bromomethyl)
SC_4032 (cyclopropylmethyl)-8- oxetan-3-yl)methanol
(dimethylamino)-3-((3- (hydroxymethyl)oxetan-3-
yl)methyl)-8-phenyl-1,3- diazaspiro[4.5]decan-2- one SC_4110
CIS-3-((3-aminooxetan-3- INT-983 tert-butyl (3- SC_4034
yl)methyl)-1- (bromomethyl)oxetan- (for step 1),
(cyclopropylmethyl)-8- 3-yl)carbamate step 2 of (dimethylamino)-8-
SC_4054 phenyl-1,3- (for step 2) diazaspiro[4.5]decan-2- one
SC_4111 CIS-3-(8- INT-983 (1-cyanocyclobutyl) SC_4032
(dimethylamino)-1-((1- methyl 4- fluorocyclopropyl)
methylbenzenesulfonate methyl)-2-oxo-8-phenyl-
1,3-diazaspiro[4.5]decan- 3-yl)-2,2- dimethylpropanenitrile SC_4112
CIS-3-(8- INT-976 2-cyano-2- SC_4032 (dimethylamino)-1-((1-
methylpropyl 4- (step 1), fluorocyclopropyl) methylbenzenesulfonate
SC_4034 methyl)-2-oxo-8-phenyl- (step 1), (step 2)
1,3-diazaspiro[4.5]decan- (1-fluorocyclopropyl) 3-yl)-2,2- methyl
4- dimethylpropanenitrile methylbenzenesulfonate (step 2) SC_5061
CIS-3-[8-(Ethyl-methyl- INT-797 3-bromo-2,2- step 1 of .sup.1HNMR
(DMSO-d6, 400 MHz, at 369.2 amino)-2-oxo-8-phenyl-
dimethyl-propionitrile INT-897 100.degree. C.), .delta. (ppm) =
7.34-7.21 (m, 1,3-diazaspiro[4.5]decan- 5H), 6.70 (bs, 1H), 3.28
(s, 2H), 3-yl]-2,2-dimethyl- 3.19 (s, 2H), 2.32-2.24 (m, 4H),
propionitrile 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-Dimethylamino-
INT-976 3-bromo-2,2-dimethyl- step 1 of .sup.1HNMR (DMSO-d6, 400
MHz), 355.2 2-oxo-8-phenyl-1,3- propionitrile INT-897 .delta. (ppm)
= 7.35-7.24 (m, 5H), 7.03 diazaspiro[4.5]decan-3- (bs, 1H), 3.25
(s, 2H), 3.15 (s, yl)-2,2-dimethyl- 2H), 2.32 (bs, 2H), 1.92 (s,
6H), propionitrile 1.82 (bs, 4H), 1.38 (bs, 2H), 1.24 (s, 6H).
SC_5065 CIS-3-[8-(Ethyl-methyl- SC_5061 methyl iodide step 1 of
.sup.1HNMR (DMSO-d6, 400 MHz), 383.2 amino)-1-methyl-2-oxo-8-
INT-953 .delta. (ppm) = 7.34-722 (m, 5H), 3.38 phenyl-1,3- (s, 2H),
3.21 (s, 2H), 2.71-2.64 diazaspiro[4.5]decan-3- (m, 5H), 2.19-2.16
(m, 4H), 1.96 yl]-2,2-dimethyl- (s, 3H), 1.37-1.30 (m, 4H), 1.25
propionitrile (s, 6H), 0.98 (t, 3H, J = 6.48 Hz). SC_5068
CIS-3-(8-Ethylamino-2- INT-1008 3-bromo-2,2-dimethyl- step 1 of
.sup.1HNMR (DMSO-d6, 400 MHz), 355.1 oxo-8-phenyl-1,3-
propionitrile INT-897 .delta. (ppm) = 7.42 (d, 12H, J = 7.32
diazaspiro[4.5]decan-3- Hz), 7.30 (t, 2H, J = 7.20 Hz),
yl)-2,2-dimethyl- 7.17 (t, 1H, J = 7.12 Hz), 6.78 (s, propionitrile
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_5080 TRANS-3-[l-
INT-1059 3-bromo-2,2- step 1 of 1HNMR at 20.degree. C. (DMSO-d6,
409.2 (Cyclopropyl-methyl)-8- dimethyl-propionitrile INT-897 400
MHz), .delta. (ppm) = 7.44-7.28 dimethylamino-2-oxo-8- (step 1),
(for step 1), (m, 5H), 3.46 (s, 2H), 3.23 (s, phenyl-1,3-
cyclopropyl- step 1 of 2H), 2.72-2.66 (m, 2H), 2.57-2.55
diazaspiro[4.5]decan-3- methylbromide INT-953 (m, 2H), 1.91 (s,
6H), 1.55-1.45 yl]-2,2-dimethyl- (step 2) (for step 2) (m, 6H),
1.27 (s, 6H), 0.51 (bs, propionitrile 1H), 0.19-0.14 (m, 2H),
(-0.22)- (-0.26) (m, 2H).
Chemical Structure of all Examples
##STR00129## ##STR00130## ##STR00131## ##STR00132## ##STR00133##
##STR00134## ##STR00135## ##STR00136## ##STR00137## ##STR00138##
##STR00139## ##STR00140## ##STR00141## ##STR00142## ##STR00143##
##STR00144## ##STR00145## ##STR00146##
[0389] Pharmacological Investigations
[0390] 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)
[0391] Human Mu-Opioid Peptide (hMOP) Receptor Binding Assay
[0392] 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).
[0393] Human Kappa-Opioid Peptide (hKOP) Receptor Binding Assay
[0394] 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 Ki values are calculated by using
the Cheng-Prusoff equation, (Cheng and Prusoff, 1973).
[0395] Human Delta-Opioid Peptide (hDOP) Receptor Binding Assay
[0396] 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 .mu.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).
[0397] Human Nociceptin/Orphanin FQ Peptide (hNOP) Receptor Binding
Assay
[0398] 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).
[0399] 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 hMOP Ki [nM] or % hNOP Ki .mu.inhibition at Example
[nM] 1M SC_4001 2.3 80.5 SC_4002 28 755 SC_4003 7.7 39.5 SC_4004 44
305 SC_4005 19 64.5 SC_4006 3.6 16 SC_4007 2.6 58 SC_4008 7.3 69.8
SC_4009 1.1 37.4 SC_4010 9.5 87 SC_4011 13 210 SC_4012 1.6 99.7
SC_4013 5.8 40.5 SC_4014 2.1 84 SC_4017 45 375 SC_4018 1.3 19.7
SC_4021 83 636.7 SC_4022 140 555 SC_4024 155 285 SC_4025 26 206
SC_4026 57 643 SC_4031 119 1430 SC_4032 345 8530 SC_4033 -- 15%@1
.mu.M SC_4034 11 245 SC_4035 69 1580 SC_4036 8 210 SC_4037 815 185
SC_4038 69 1290 SC_4039 3 165 SC_4040 19 270 SC_4041 4 125 SC_4042
11 290 SC_4043 4 124 SC_4044 19 1065 SC_4045 17 415 SC_4046 15 655
SC_4047 8 265 SC_4048 46 805 SC_4049 11 220 SC_4050 19 255 SC_4051
21 770 SC_4052 3 175 SC_4053 34 1350 SC_4054 26 1305 SC_4055 54
1865 SC_4056 10 1755 SC_4057 3 1050 SC_4058 15 540 SC_4059 710 9%@1
.mu.M SC_4060 1170 5%@1 .mu.M SC_4061 710 9%@1 .mu.M SC_4062 27
1810 SC_4063 15 2910 SC_4064 5 495 SC_4066 40 3045 SC_4067 12 615
SC_4068 13 985 SC_4069 140 6900 SC_4070 140 8% SC_4071 1 63 SC_4072
10 255 SC_4073 6 300 SC_4074 12 460 SC_4075 1 39 SC_4076 235 17%
SC_4077 75 3230 SC_4078 125 74 SC_4079 6 415 SC_4080 145 4145
SC_4081 10 765 SC_4082 10 270 SC_4083 10 235 SC_4084 118 2465
SC_4085 3 495 SC_4086 6 570 SC_4087 12 535 SC_4088 6 935 SC_4089 64
275 SC_4090 6 520 SC_4091 0.4 76 SC_4092 16 17 SC_4093 17 1000
SC_4094 23 1980 SC_4095 8 630 SC_4096 36 330 SC_4097 114 4355
SC_4098 395 96 SC_5061 705 6%@1 .mu.M SC_5062 84 2925 SC_5063 690
4%@1 .mu.M SC_5065 0%@1 .mu. 13%@1 .mu.M M (DOP 40%) SC_5068 0%@1
.mu. 8%@1 .mu.M M (KOP 40%) SC_5075 10 305 SC_5080 24 230
[0400] Protocol for [.sup.35S]GTP.gamma.S Functional
NOP/MOP/KOP/DOP Assays
[0401] 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. 93-0264C.sub.2, 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.).
[0402] 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 MgCl2, 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.).
[0403] 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.
[0404] 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.
* * * * *