U.S. patent application number 10/704524 was filed with the patent office on 2004-11-18 for substituted cyclohexane-1,4-diamine compounds with anti-diarrhea and peripheral analgesic activity.
This patent application is currently assigned to Gruenenthal GmbH. Invention is credited to Friderichs, Elmar Josef, Hinze, Claudia, Koegel, Babette-Yvonne, Sundermann, Bernd.
Application Number | 20040229872 10/704524 |
Document ID | / |
Family ID | 7684562 |
Filed Date | 2004-11-18 |
United States Patent
Application |
20040229872 |
Kind Code |
A1 |
Friderichs, Elmar Josef ; et
al. |
November 18, 2004 |
Substituted cyclohexane-1,4-diamine compounds with anti-diarrhea
and peripheral analgesic activity
Abstract
The use of substituted cyclohexan-1,4-diamine compounds in
pharmaceutical compositions and for the treatment of diarrhea or
irritable bowel diseases or as immunotherapeutic agents or
peripheral analgesics, especially for treating burn pains,
peripheral operation pains, pains generated by inflammation of soft
tissues or inflammatory arthropathies, especially rheumatisms.
Inventors: |
Friderichs, Elmar Josef;
(Stolberg, DE) ; Sundermann, Bernd; (Aachen,
DE) ; Hinze, Claudia; (Aachen, DE) ; Koegel,
Babette-Yvonne; (Langerwehe-Hamich, DE) |
Correspondence
Address: |
CROWELL & MORING LLP
INTELLECTUAL PROPERTY GROUP
P.O. BOX 14300
WASHINGTON
DC
20044-4300
US
|
Assignee: |
Gruenenthal GmbH
Zieglerstrasse 6
Aachen
DE
52078
|
Family ID: |
7684562 |
Appl. No.: |
10/704524 |
Filed: |
November 10, 2003 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
10704524 |
Nov 10, 2003 |
|
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PCT/EP02/05122 |
May 9, 2002 |
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Current U.S.
Class: |
514/237.5 ;
514/255.03; 514/317; 514/408; 514/579 |
Current CPC
Class: |
A61P 9/00 20180101; A61P
15/18 20180101; A61P 25/08 20180101; A61P 9/10 20180101; A61P 37/00
20180101; A61P 25/06 20180101; A61P 15/10 20180101; A61P 3/04
20180101; A61P 19/02 20180101; A61P 23/00 20180101; A61P 25/22
20180101; A61P 1/12 20180101; A61P 25/00 20180101; A61P 25/32
20180101; A61P 27/16 20180101; A61P 25/24 20180101; A61K 31/132
20130101; A61K 31/38 20130101; A61P 21/02 20180101; A61P 25/28
20180101; A61P 25/02 20180101; A61P 25/04 20180101; A61P 25/36
20180101; A61K 31/165 20130101; A61P 1/14 20180101; A61P 17/04
20180101; A61P 25/30 20180101; A61P 7/00 20180101; A61P 43/00
20180101; A61P 9/12 20180101; A61P 37/02 20180101; A61P 13/02
20180101; A61K 31/404 20130101; A61K 31/425 20130101; A61P 29/00
20180101; A61P 1/00 20180101; A61K 31/13 20130101; A61P 9/04
20180101 |
Class at
Publication: |
514/237.5 ;
514/255.03; 514/317; 514/408; 514/579 |
International
Class: |
A61K 031/537; A61K
031/495; A61K 031/445; A61K 031/16; A61K 031/13 |
Foreign Application Data
Date |
Code |
Application Number |
May 9, 2001 |
DE |
101 23 163.6 |
Claims
1. A method of treating diarrhea or irritable bowel disease or
administering immunotherapeutic treatment to a patient, said method
comprising administering to said patient a pharmaceutically
effective amount of a substituted cyclohexane-1,4-diamine compound
corresponding to formula I 10wherein R.sup.1 and R.sup.2 are
independently selected from the group consisting of H;
C.sub.1-8-alkyl and C.sub.3-8-cycloalkyl, each saturated or
unsaturated, branched or unbranched, singly or multiply substituted
or unsubstituted; aryl and heteroaryl, each singly or multiply
substituted or unsubstituted; and aryl, C.sub.3-8-cycloalkyl and
heteroaryl each bound via C.sub.1-3-alkylene and each singly or
multiply substituted or unsubstituted; or R.sup.1 and R.sup.2
together form a ring and denote CH.sub.2CH.sub.2OCH.sub.2CH.sub.2,
CH.sub.2CH.sub.2NR.sup.6CH.- sub.2CH.sub.2 or (CH.sub.2).sub.3-6,
where R.sup.6 is selected from the group consisting of H;
C.sub.1-8-alkyl and C.sub.3-8-cycloalkyl, each saturated or
unsaturated, branched or unbranched, singly or multiply substituted
or unsubstituted; aryl and heteroaryl, each singly or multiply
substituted or unsubstituted; and aryl, C.sub.3-8-cycloalkyl and
heteroaryl, each bound via C.sub.1-3-alkylene and each singly or
multiply substituted or unsubstituted; R.sup.3 is selected from the
group consisting of C.sub.1-8-alkyl and C.sub.3-8-cycloalkyl, each
saturated or unsaturated, branched or unbranched, singly or
multiply substituted or unsubstituted; aryl and heteroaryl, each
unsubstituted or singly or multiply substituted; and aryl,
C.sub.3-8-cycloalkyl and heteroaryl, each bound via a saturated or
unsaturated, branched or unbranched, substituted or unsubstituted
C.sub.1-4-alkylene group and each unsubstituted or singly or
multiply substituted; R.sup.4 is selected from the group consisting
of H; C.sub.1-8-alkyl, saturated or unsaturated, branched or
unbranched, singly or multiply substituted or unsubstituted;
C(X)R.sup.7; C(X)NR.sup.7R.sup.8; C(X)OR.sup.9; C(X)SR.sup.9, and
S(O.sub.2) R.sup.9, where X=O or S; R.sup.7 is selected from the
group consisting of H; C.sub.1-8-alkyl and C.sub.3-8-cycloalkyl,
each saturated or unsaturated, branched or unbranched, singly or
multiply substituted or unsubstituted; aryl and heteroaryl, each
unsubstituted or singly or multiply substituted; and aryl,
C.sub.3-8-cycloalkyl and heteroaryl, each bound via a saturated or
unsaturated, branched or unbranched, substituted or unsubstituted
C.sub.1-4-alkylene group and each unsubstituted or singly or
multiply substituted; and R.sup.8 is selected from the group
consisting of H and C.sub.1-4-alkyl that is saturated or
unsaturated, branched or unbranched, singly or multiply substituted
or unsubstituted; or R.sup.7 and R.sup.8 together form a ring and
denote CH.sub.2CH.sub.2OCH.sub.2CH.sub.2,
CH.sub.2CH.sub.2NR.sup.10CH.sub.2CH.su- b.2 or (CH.sub.2).sub.3-6,
where R.sup.10 is selected from the group consisting of H;
C.sub.1-8-alkyl or C.sub.3-8-cycloalkyl, each saturated or
unsaturated, branched or unbranched, singly or multiply substituted
or unsubstituted; aryl and heteroaryl, each singly or multiply
substituted or unsubstituted; and aryl, C.sub.3-8-cycloalkyl and
heteroaryl, each bound via C.sub.1-3-alkylene and each singly or
multiply substituted or unsubstituted; and R.sup.9 is selected from
the group consisting of C.sub.1-8-alkyl and C.sub.3-8-cycloalkyl,
each saturated or unsaturated, branched or unbranched, singly or
multiply substituted or unsubstituted; aryl and heteroaryl, each
unsubstituted or singly or multiply substituted; and aryl,
C.sub.3-8-cycloalkyl and heteroaryl, each bound via a saturated or
unsaturated, branched or unbranched, substituted or unsubstituted
C.sub.1-4-alkylene group and each unsubstituted or singly or
multiply substituted; and R.sup.5 is selected from the group
consisting of C.sub.3-8-cycloalkyl, aryl and heteroaryl, each
unsubstituted or singly or multiply substituted;
--CHR.sup.11R.sup.12; --CHR.sup.11--CH.sub.2R.sup.12;
--CHR.sup.11--CH.sub.2--CH.sub.2R.sup.12;
--CHR.sup.11--CH.sub.2--CH.sub.2--CH.sub.2R.sup.12; --C(Y)R.sup.12;
--C(Y)--CH.sub.2R.sup.12; --C(Y)--CH.sub.2--CH.sub.2R .sup.12, and
--C(Y)--CH.sub.2--CH.sub.2--CH.sub.2R.sup.12, where Y=O, S or
H.sub.2; R.sup.11 is selected from the group consisting of H;
C.sub.1-7-alkyl that is saturated or unsaturated, branched or
unbranched, singly or multiply substituted or unsubstituted; and
C(O)O--C.sub.1-6-alkyl that is saturated or unsaturated, branched
or unbranched, singly or multiply substituted or unsubstituted; and
R.sup.12 is selected from the group consisting of H;
C.sub.3-8-cycloalkyl, aryl or heteroaryl, each unsubstituted or
singly or multiply substituted; or R.sup.4 and R.sup.5 together
form a heterocycle with from 3 to 8 atoms in the ring, which is
saturated or unsaturated, singly or multiply substituted or
unsubstituted, and which may optionally be condensed with further
rings, or a salt thereof with a physiologically acceptable acid or
base.
2. A method according to claim 1, wherein said compound is in the
form of a racemate.
3. A method according to claim 1, wherein said compound is in the
form of a pure stereoisomer.
4. A method according to claim 3, wherein said stereoisomer is in
the form of a pure enantiomer.
5. A method according to claim 3, wherein said stereoisomer is in
the form of a pure diastereomer.
6. A method according to claim 1, wherein said compound is the the
form of mixture of stereoisomers in an arbitrary mixing ratio.
7. A method according to claim 1, wherein said compound is in the
form of a free base.
8. A method according to claim 1, wherein said compound is in the
form of a salt with a physiologically compatible acid.
9. A method according to claim 1, wherein said compound is in the
form of a solvate.
10. (canceled)
11. A method according to claim 1, wherein in said compound R.sup.1
and R.sup.2 are not both H.
12. A method according to claim 1, wherein R.sup.1 and R.sup.2 in
said compound are independently selected from the group consisting
of H, and C.sub.1-8-alkyl that is saturated or unsaturated,
branched or unbranched, singly or multiply substituted or
unsubstituted, with the proviso that R.sup.1 and R.sup.2 are not
both H, or R.sup.1 and R.sup.2 together form a ring and denote
CH.sub.2CH.sub.2OCH.sub.2CH.sub.2,
CH.sub.2CH.sub.2NR.sup.6CH.sub.2CH.sub.2 or (CH.sub.2).sub.3-6,
where R.sup.6 is selected from the group consisting of H and
C.sub.1-8-alkyl that is saturated or unsaturated, branched or
unbranched, singly or multiply substituted or unsubstituted.
13. A method according to claim 12, wherein R.sup.1 and R.sup.2 are
independently selected from the group consisting of H, and
C.sub.1-4-alkyl which is saturated or unsaturated, branched or
unbranched, singly or multiply substituted or unsubstituted, with
the proviso that R.sup.1 and R.sup.2 are not both H, or wherein
R.sup.1 and R.sup.2 together form a ring and denote
(CH.sub.2).sub.4-5.
14. (cancelled)
15. A method according to claim 1, wherein R.sup.3 in said compound
is selected from the group consisting of C.sub.3-8-cycloalkyl, aryl
and heteroaryl, each unsubstituted or singly or multiply
substituted; and aryl, C.sub.3-8-cycloalkyl and heteroaryl, each
bound via a saturated or unsaturated, unbranched, substituted or
unsubstituted C.sub.1-2-alkylene group and each unsubstituted or
singly or multiply substituted.
16. A method according to claim 15, wherein R.sup.3 in said
compound is selected from the group consisting of
C.sub.5-6-cycloalkyl, phenyl, naphthyl, anthracenyl, thiophenyl,
benzothiophenyl, furyl, benzofuranyl, benzodioxolanyl, indolyl,
indanyl, benzodioxanyl, pyrrolyl, pyrimidyl, and pyrazinyl, each
unsubstituted or singly or multiply substituted; and
C.sub.5-6-cycloalkyl, phenyl, naphthyl, anthracenyl, thiophenyl,
benzothiophenyl, pyridyl, furyl, benzofuranyl, benzodioxolanyl,
indolyl, indanyl, benzodioxanyl, pyrrolyl, pyrimidyl and pyrazinyl,
each bound via a saturated, unbranched C.sub.1-2-alkylene group and
each unsubstituted or singly or multiply substituted.
17. A method according to claim 15, wherein R.sup.3 in said
compound is selected from the group consisting of phenyl, furyl,
thiophenyl, cyclohexanyl, naphthyl, benzofuranyl, indolyl, indanyl,
benzodioxanyl, benzodioxolanyl, pyrrolyl, pyridyl, pyrazinyl and
benzothiophenyl, each unsubstituted or singly or multiply
substituted; and phenyl, furyl and thiophenyl, each bound via a
saturated, unbranched C.sub.1-2-alkylene group and each
unsubstituted or singly or multiply substituted.
18. A method according to claim 1, wherein R.sup.4 in said compound
is H.
19. A method according to claim 1, wherein R.sup.4 in said compound
is selected from the group consisting of H, C(X)R.sup.7,
C(X)NR.sup.7R.sup.8, C(X)OR.sup.9, C(X)SR.sup.9 and
S(O.sub.2)R.sup.9, where X=O or S.
20. A method according to claim 19, wherein R.sup.4 in said
compound is selected from the group consisting of H, C(X)R.sup.7,
C(X)NR.sup.7R.sup.8 and C(X)OR.sup.9, where X=O.
21. A method according to claim 19, wherein R.sup.4 in said
compound is H or C(O)R.sup.7, where R.sup.7 is H or C.sub.1-8-alkyl
that is saturated or unsaturated, branched or unbranched, singly or
multiply substituted or unsubstituted.
22. (canceled)
23. (canceled)
24. A method according to claim 1, wherein in said compound R.sup.4
and R.sup.5 together with the N-atom to which they are bound form a
heterocyclic ring containing from 3 to 8 atoms, which is saturated
or unsaturated; singly or multiply substituted or
unsubstituted.
25. A method according to claim 24, wherein said heterocyclic ring
contains from 5 to 7 atoms and in addition to the N-atom to which
R4 and R5 are bound contains 0 to 1 heteroatom selected from the
group consisting of N, S and O.
26. A method according to claim 24, wherein the heterocyclic ring
formed by R.sup.4 and R.sup.5 is condensed with at least one
further ring.
27. (canceled)
28. (canceled)
29. A method according to claim 26, wherein the heterocyclic ring
formed by R.sup.4 and R.sup.5 is condensed with two further rings
to produce 11
30. A method according to claim 1, wherein R.sup.4 in said compound
is selected from the group consisting of H, and C.sub.1-8-alkyl
that is saturated or unsaturated, branched or unbranched, and
singly or multiply substituted or unsubstituted.
31. A method according to claim 30, wherein R.sup.4 in said
compound is selected from the group consisting of H, and
C.sub.1-6-alkyl that is saturated or unsaturated, branched or
unbranched, and singly or multiply substituted or
unsubstituted.
32. (canceled)
33. A method according to claim 1, wherein R.sup.5 in said compound
is selected from the group consisting of C.sub.1-8-cycloalkyl, aryl
and heteroaryl, each unsubstituted or singly or multiply
substituted.
34. A method according to claim 33, wherein R.sup.5 in said
compound is selected from the group consisting of cyclobutyl,
cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl,
anthracenyl, indolyl, naphthyl, benzofuranyl, benzothiophenyl,
indanyl, benzodioxanyl, benzodioxolanyl, acenaphthyl, carbazolyl,
phenyl, thiophenyl, furyl, pyridyl, pyrrolyl, pyrazinyl, pyrimidyl,
fluorenyl, fluoranthenyl, benzothiazolyl, benzotriazolyl,
benzo[1,2,5]thiazolyl, 1,2-dihydroacenaphthenyl, pyridinyl,
furanyl, benzofuranyl, pyrazolinonyl, oxopyrazolinonyl, dioxolanyl,
adamantyl, pyrimidinyl, quinolinyl, isoquinolinyl, phthalazinyl and
quinazolinyl, each unsubstituted or singly or multiply
substituted.
35. (canceled)
36. A method according to claim 1, wherein R.sup.5 in said compound
is selected from the group consisting of --CHR.sup.11R.sup.12,
--CHR.sup.11--CH.sub.2R.sup.12,
--CHR.sup.11--CH.sub.2CH.sub.2R.sup.12,
--CHR.sup.11--CH.sub.2--CH.sub.2--CH.sub.2R.sup.12, --C(Y)R.sup.12,
--C(Y)--CH.sub.2R.sup.12, --C(Y)--CH.sub.2--CH.sub.2R.sup.12, and
--C(Y)--CH.sub.2--CH.sub.2--CH.sub.2R.sup.12, where Y=O, S or
H.sub.2.
37. A method according to claim 36, wherein R.sup.5 in said
compound is selected from the group consisting of
--CHR.sup.11R.sup.12, --CHR.sup.11--CH.sub.2R.sup.12,
--CHR.sup.11--CH.sub.2--CH.sub.2R.sup.12, --C(Y)R.sup.12,
--C(Y)--CH.sub.2R.sup.12, and --C(Y)--CH.sub.2--CH.sub.2R- .sup.12,
where Y=O or S.
38. (canceled)
39. A method according to claim 36, wherein R.sup.11 in said
compound is selected from the group consisting of H;
C.sub.1-4-alkyl that is saturated or unsaturated, branched or
unbranched, and singly or multiply substituted or unsubstituted;
and C(O)O--C.sub.1-4-alkyl that is saturated or unsaturated,
branched or unbranched, and singly or multiply substituted or
unsubstituted.
40. (canceled)
41. (canceled)
42. A method according to claim 36, wherein R.sup.12 in said
compound is selected from the group consisting of
C.sub.3-8-cycloalkyl, aryl and heteroaryl, each unsubstituted or
singly or multiply substituted.
43. (canceled)
44. (canceled)
45. A method according to claim 1, wherein said compound is
selected from the group consisting of: potassium
(S)-2-(4-dimethylamino-4-phenylcyclohe-
xylamino)-3-(1H-indol-3-yl)-propionate, non-polar diastereomer;
potassium
rac-2-(4-dimethylamino-4-phenylcyclohexylamino)-3-(5-fluoro-1H-indol-3-yl-
)-propionate, non-polar diastereomer; potassium
rac-2-(4-dimethylamino-4-p-
henylcyclohexylamino)-3-(6-fluoro-1H-indol-3-yl)-propionate,
non-polar diastereomer; potassium
(S)-2-(4-dimethylamino-4-thiophen-2-yl-cyclohexyl-
amino)-3-(1H-indol-3-yl)-propionate, non-polar diastereomer;
(S)-2-(4-dimethylamino-4-thiophen-2-yl-cyclohexylamino)-3-(1H-indol-3-yl)-
-propionic acid hydrochloride, polar diastereomer;
(S)-2-(4-dimethylamino-- 4-phenylcyclohexylamino)-3-phenylpropionic
acid hydrochloride, non-polar diastereomer; potassium
rac-2-(4-dimethylamino-4-phenylcyclohexylamino)-4- -phenylbutyrate,
non-polar diastereomer; rac-2-(4-dimethylamino-4-phenylcy-
clohexylamino)-4-phenylbutyric acid hydrochloride, polar
diastereomer;
(R)-2-(4-dimethylamino-4-phenylcyclohexylamino)-3-(1H-indol-3-yl)-propion-
ic acid hydrochloride, non-polar diastereomer;
(R)-2-(4-dimethylamino-4-ph- enylcyclohexylamino)-3-phenylpropionic
acid hydrochloride, non-polar diastereomer, and
rac-2-(4-dimethylamino-4-phenylcyclohexylamino)-3-(3-hy-
droxyphenyl)-propionic acid hydrochloride.
46. A method of treating peripheral pain in a patient, said method
comprising administering to said patient an effective peripheral
analgesically effective amount of a substituted
cyclohexane-1,4-diamine compound corresponding to formula I
12wherein R.sup.1 and R.sup.2 are independently selected from the
group consisting of H; C.sub.1-8-alkyl and C.sub.3-8-cycloalkyl,
each saturated or unsaturated, branched or unbranched, singly or
multiply substituted or unsubstituted; aryl and heteroaryl, each
singly or multiply substituted or unsubstituted; and aryl,
C.sub.3-8-cycloalkyl and heteroaryl each bound via
C.sub.1-3-alkylene and each singly or multiply substituted or
unsubstituted; or R.sup.1 and R.sup.2 together form a ring and
denote CH.sub.2CH.sub.2OCH.sub.2CH.sub.2,
CH.sub.2CH.sub.2NR.sup.6CH.sub.2CH.sub- .2 or (CH.sub.2).sub.3-6,
where R.sup.6 is selected from the group consisting of H;
C.sub.1-8-alkyl and C.sub.3-8-cycloalkyl, each saturated or
unsaturated, branched or unbranched, singly or multiply substituted
or unsubstituted; aryl and heteroaryl, each singly or multiply
substituted or unsubstituted; and aryl, C.sub.3-8-cycloalkyl and
heteroaryl, each bound via C.sub.1-3-alkylene and each singly or
multiply substituted or unsubstituted; R.sup.3 is selected from the
group consisting of C.sub.1-8-alkyl and C.sub.3-8-cycloalkyl, each
saturated or unsaturated, branched or unbranched, singly or
multiply substituted or unsubstituted; aryl and heteroaryl, each
unsubstituted or singly or multiply substituted; and aryl,
C.sub.3-8-cycloalkyl and heteroaryl, each bound via a saturated or
unsaturated, branched or unbranched, substituted or unsubstituted
C.sub.1-4-alkylene group and each unsubstituted or singly or
multiply substituted; R.sup.4 is selected from the group consisting
of H; C(X)R.sup.7; C(X)NR.sup.7R.sup.8; C(X)OR.sup.9; C(X)SR.sup.9,
and S(O.sub.2)R.sup.9, where X=O or S; R.sup.7 is selected from the
group consisting of H; C.sub.1-8-alkyl and C.sub.3-8-cycloalkyl,
each saturated or unsaturated, branched or unbranched, singly or
multiply substituted or unsubstituted; aryl and heteroaryl, each
unsubstituted or singly or multiply substituted; and aryl,
C.sub.3-8-cycloalkyl and heteroaryl, each bound via a saturated or
unsaturated, branched or unbranched, substituted or unsubstituted
C.sub.1-4-alkylene group and each unsubstituted or singly or
multiply substituted; and R.sup.8 is selected from the group
consisting of H and C.sub.1-4-alkyl that is saturated or
unsaturated, branched or unbranched, singly or multiply substituted
or unsubstituted; or R.sup.7 and R.sup.8 together form a ring and
denote CH.sub.2CH.sub.2OCH.sub.2CH.sub.2,
CH.sub.2CH.sub.2NR.sup.10CH.sub.2CH.su- b.2 or (CH.sub.2).sub.3-6,
where R.sup.10 is selected from the group consisting of H;
C.sub.1-8-alkyl or C.sub.3-8-cycloalkyl, each saturated or
unsaturated, branched or unbranched, singly or multiply substituted
or unsubstituted; aryl and heteroaryl, each singly or multiply
substituted or unsubstituted; and aryl, C.sub.3-8-cycloalkyl and
heteroaryl, each bound via C.sub.1-3-alkylene and each singly or
multiply substituted or unsubstituted; and R.sup.9 is selected from
the group consisting of C.sub.1-8-alkyl and C.sub.3-8-cycloalkyl,
each saturated or unsaturated, branched or unbranched, singly or
multiply substituted or unsubstituted; aryl and heteroaryl, each
unsubstituted or singly or multiply substituted; and aryl,
C.sub.3-8-cycloalkyl and heteroaryl, each bound via a saturated or
unsaturated, branched or unbranched, substituted or unsubstituted
C.sub.1-4-alkylene group and each unsubstituted or singly or
multiply substituted; and R.sup.5 is selected from the group
consisting of C.sub.3-8-cycloalkyl, aryl and heteroaryl, each
unsubstituted or singly or multiply substituted;
--CHR.sup.11R.sup.12; --CHR.sup.11--CH.sub.2R.sup.12,
--CHR.sup.11--CH.sub.2--CH.sub.2R.sup.12,
--CHR.sup.11--CH.sub.2--CH.sub.2--CH.sub.2R.sup.12; --C(Y)R.sup.12;
--C(Y)--CH.sub.2R.sup.12, --C(Y)--CH.sub.2--CH.sub.2R.sup.12, and
--C(Y)--CH.sub.2--CH.sub.2--CH.sub.2R.sup.12, where Y=O, S or
H.sub.2; R.sup.11 is selected from the group consisting of H;
C.sub.1-7-alkyl that is saturated or unsaturated, branched or
unbranched, singly or multiply substituted or unsubstituted; and
C(O)O--C.sub.1-6-alkyl that is saturated or unsaturated, branched
or unbranched, singly or multiply substituted or unsubstituted; and
R.sup.12 is selected from the group consisting of H;
C.sub.3-8-cycloalkyl, aryl or heteroaryl, each unsubstituted or
singly or multiply substituted; or a salt thereof with a
physiologically acceptable acid or base.
47. (canceled)
48. A method according to claim 46, wherein said compound is in the
form of a pure stereoisomer.
49. (canceled)
50. (canceled)
51. (canceled)
52. (canceled)
53. (canceled)
54. A method according to claim 46, wherein said compound is in the
form of a solvate.
55. (canceled)
56. (canceled)
57. A method according to claim 46, wherein R.sup.1 and R.sup.2 in
said compound are independently selected from the group consisting
of H, and C.sub.1-8-alkyl that is saturated or unsaturated,
branched or unbranched, singly or multiply substituted or
unsubstituted, with the proviso that R.sup.1 and R.sup.2 are not
both H, or R.sup.1 and R.sup.2 together form a ring and denote
CH.sub.2CH.sub.2OCH.sub.2CH.sub.2,
CH.sub.2CH.sub.2NR.sup.6CH.sub.2CH.sub.2 or (CH.sub.2).sub.3-6,
where R.sup.6 is selected from the group consisting of H and
C.sub.1-8-alkyl that is saturated or unsaturated, branched or
unbranched, singly or multiply substituted or unsubstituted.
58. (canceled)
59. (canceled)
60. A method according to claim 46, wherein R.sup.3 in said
compound is selected from the group consisting of
C.sub.3-8-cycloalkyl, aryl and heteroaryl, each unsubstituted or
singly or multiply substituted; and aryl, C.sub.3-8-cycloalkyl and
heteroaryl, each bound via a saturated or unsaturated, unbranched,
substituted or unsubstituted C.sub.1-2-alkylene group and each
unsubstituted or singly or multiply substituted.
61. (canceled)
62. (canceled)
63. (canceled)
64. A method according to claim 46, wherein R.sup.4 in said
compound is selected from the group consisting of H, C(X)R.sup.7,
C(X)NR.sup.7R.sup.8 and C(X)OR.sup.9, where X=O.
65. (canceled)
66. (canceled)
67. (canceled)
68. A method according to claim 46, wherein R.sup.5 in said
compound is selected from the group consisting of
C.sub.3-8-cycloalkyl, aryl and heteroaryl, each unsubstituted or
singly or multiply substituted.
69. (canceled)
70. (canceled)
71. A method according to claim 46, wherein R.sup.5 in said
compound is selected from the group consisting of
--CHR.sup.11--R.sup.12, --CHR.sup.11--CH.sub.2R.sup.12,
--CHR.sup.11--CH.sub.2--CH.sub.2R.sup.12,
--CHR.sup.11--CH.sub.2--CH.sub.2--CH.sub.2R.sup.12, --C(Y)R.sup.12,
--C(Y)--CH.sub.2R.sub.12, --C(Y)--CH.sub.2--CH.sub.2R.sup.12, and
--C(Y)--CH.sub.2--CH.sub.2--CH.sub.2R.sup.12, where Y=O, S or
H.sub.2.
72. (canceled)
73. (canceled)
74. (canceled)
75. (canceled)
76. (canceled)
77. (canceled)
78. (canceled)
79. (canceled)
80. A method according to claim 46, wherein said compound is
selected from the group consisting of: potassium
(S)-2-(4-dimethylamino-4-phenylcyclohe-
xylamino)-3-(1H-indol-3-yl)-propionate, non-polar diastereomer;
potassium
rac-2-(4-dimethylamino-4-phenylcyclohexylamino)-3-(5-fluoro-1H-indol-3-yl-
)-propionate, non-polar diastereomer; potassium
rac-2-(4-dimethylamino-4-p-
henylcyclohexylamino)-3-(6-fluoro-1H-indol-3-yl)-propionate,
non-polar diastereomer; potassium
(S)-2-(4-dimethylamino-4-thiophen-2-yl-cyclohexyl-
amino)-3-(1H-indol-3-yl)-propionate, non-polar diastereomer;
(S)-2-(4-dimethylamino-4-thiophen-2-yl-cyclohexylamino)-3-(1H-indol-3-yl)-
-propionic acid hydrochloride, polar diastereomer;
(S)-2-(4-dimethylamino-- 4-phenylcyclohexylamino)-3-phenylpropionic
acid hydrochloride, non-polar diastereomer; potassium
rac-2-(4-dimethylamino-4-phenylcyclohexylamino)-4- -phenylbutyrate,
non-polar diastereomer; rac-2-(4-dimethylamino-4-phenylcy-
clohexylamino)-4-phenylbutyric acid hydrochloride, polar
diastereomer;
(R)-2-(4-dimethylamino-4-phenylcyclohexylamino)-3-(1H-indol-3-yl)-propion-
ic acid hydrochloride, non-polar diastereomer;
(R)-2-(4-dimethylamino-4-ph- enylcyclohexylamino)-3-phenylpropionic
acid hydrochloride, non-polar diastereomer, and
rac-2-(4-dimethylamino-4-phenylcyclohexylamino)-3-(3-hy-
droxyphenyl)-propionic acid hydrochloride.
81. A method according to claim 46, wherein said peripheral pain is
selected from the group consisting of burn pains, pain in
inflammation of soft tissues, peripheral operation pain and
inflammatory joint disease pain.
82. (canceled)
Description
CROSS REFERENCE TO RELATED APPLICATIONS
[0001] This application is a continuation of international patent
application no. PCT/EP02/05122, filed May 9, 2002, designating the
United States of America, and published in German as WO 02/089783,
the entire disclosure of which is incorporated herein by reference.
Priority is claimed based on Federal Republic of Germany patent
application no. DE 101 23 163.6, filed May 9, 2001.
BACKGROUND OF THE INVENTION
[0002] The present invention relates to the use of substituted
cyclohexane-1,4-diamine compounds for the production of medicaments
and for the treatment of diarrhea or irritable bowel diseases or
for use as an immunotherapeutic agent or as a peripheral analgesic,
in particular for the treatment of burn pains, pains in
inflammatory joint diseases, inflammation of soft tissues or
peripheral operation pain.
[0003] Peripheral .mu.-opiate receptors have for a long time been
the subject of various investigations. Suppression of diarrhea in
acute and chronic diarrhea and other diseases of the
gastrointestinal tract that are associated with a hypersecretion
and hypermotility of the intestinal tract are the main
therapeutically utilisable effects peripherally transmitted via
these receptors. These various diseases are summarised under the
generic name "irritable bowel diseases". .mu.-opioids are extremely
suitable for the treatment of these diseases and have long been
therapeutically employed (e.g. opium tincture), though they are
subject to a considerable restriction due to their side effects on
the central nervous system, in particular due to their potential
for addiction and dependence. Progress in the use of opioids in the
treatment of diarrhea was provided by the drug loperamide, in which
the opioid properties affecting the central nervous system are
absent and which therefore has no potential for addiction and
dependence and which is no longer subject to legislation governing
the use of narcotics. A decisive factor is that the action is
transmitted peripherally and not via the central nervous
system.
[0004] In addition to their use as antidiarrhea agents and in other
gastrointestinal disorders substances with a high affinity for the
.mu.-receptor may be used as peripherally active analgesics.
According to recent investigations, in particular in the team led
by Stein, it was found that, in addition to the opiate receptors in
the central nervous system, opiate receptors in the periphery are
also involved in suppressing pain. These peripheral pain-relevant
opiate receptors are in some cases induced only within the context
of the underlying disease by immunological reactions or
inflammation processes and may then be activated, in addition to
the central nervous system opioid receptors, in suppressing pain.
Typical types of pain in which peripheral opiate receptors play a
role are burn pains, pain in inflammatory joint diseases,
inflammation of soft tissues and operation pain in orthopaedic
interventions. Rheumatic pains also play a role.
[0005] In many in vitro and in vivo models .mu.-opioids exhibit
immunomodulating properties. Generally an immunosuppressive effect
is seen, which is transmitted via peripheral opioid systems and
which could be used for therapeutic purposes.
SUMMARY OF THE INVENTION
[0006] The object of the present invention was to provide
medicaments that are suitable for the treatment of diarrhea or
irritable bowel diseases or for use as an immunotherapeutic agent
or as a peripheral analgesic, in particular for the treatment of
burn pains, pain in inflammatory joint diseases, inflammation of
soft tissues or peripheral operation pain. In particular the
compounds used for this purpose are peripherally active
.mu.-agonists without any action on the central nervous system.
[0007] The present invention accordingly provides for the use of
substituted cyclohexane-1,4-diamine compounds according to the
general formula I 1
[0008] wherein
[0009] R.sup.1 and R.sup.2 independently of one another are
selected from H; C.sub.1-8-alkyl or C.sub.3-8-cycloalkyl, in each
case saturated or unsaturated, branched or unbranched, singly or
multiply substituted or unsubstituted; aryl or heteroaryl, in each
case singly or multiply substituted or unsubstituted, or aryl,
C.sub.3-8-cycloalkyl or heteroaryl bound via C.sub.1-3-alkylene, in
each case singly or multiply substituted or unsubstituted, wherein
R.sup.1 and R.sup.2 may not both be H, or the radicals R.sup.1 and
R.sup.2 together form a ring and denote
CH.sub.2CH.sub.2OCH.sub.2CH.sub.2,
CH.sub.2CH.sub.2NR.sup.6CH.sub.2CH.sub- .2 or
(CH.sub.2).sub.3-6,
[0010] where R.sup.6 is selected from H; C.sub.1-8-alkyl or
C.sub.3-8-cycloalkyl, in each case saturated or unsaturated,
branched or unbranched, singly or multiply substituted or
unsubstituted; aryl or heteroaryl, in each case singly or multiply
substituted or unsubstituted; or aryl, C.sub.3-8-cycloalkyl or
heteroaryl bound via C.sub.1-3-alkylene, in each case singly or
multiply substituted or unsubstituted;
[0011] R.sup.3 is selected from C.sub.1-8-alkyl or
C.sub.3-8-cycloalkyl, in each case saturated or unsaturated,
branched or unbranched, singly or multiply substituted or
unsubstituted; aryl, heteroaryl, in each case unsubstituted or
singly or multiply substituted; aryl, C.sub.3-8-cycloalkyl or
heteroaryl bound via a saturated or unsaturated, branched or
unbranched, substituted or unsubstituted C.sub.1-4-alkyl group, and
in each case unsubstituted or singly or multiply substituted;
[0012] R.sup.4 is selected from H, C.sub.1-8-alkyl, saturated or
unsaturated, branched or unbranched, singly or multiply substituted
or unsubstituted, or C(X)R.sup.7, C(X)NR.sup.7R.sup.8,
C(X)OR.sup.9, C(X)SR.sup.9, S(O.sub.2)R.sup.9
[0013] where X=O or S,
[0014] where R.sup.7 is selected from H, C.sub.1-8-alkyl or
C.sub.3-8-cycloalkyl, in each case saturated or unsaturated,
branched or unbranched, singly or multiply substituted or
unsubstituted; aryl, heteroaryl, in each case unsubstituted or
singly or multiply substituted; aryl, C.sub.3-8-cycloalkyl or
heteroaryl bound via a saturated or unsaturated, branched or
unbranched, substituted or unsubstituted C.sub.1-4-alkyl group, and
in each case unsubstituted or singly or multiply substituted;
[0015] where R.sup.8 is selected from H, C.sub.1-4-alkyl that is
saturated or unsaturated, branched or unbranched, singly or
multiply substituted or unsubstituted, or
[0016] the radicals R.sup.7 and R.sup.8 together form a ring and
denote CH.sub.2CH.sub.2OCH.sub.2CH.sub.2,
CH.sub.2CH.sub.2NR.sup.10CH.sub.2CH.su- b.2 or
(CH.sub.2).sub.3-6,
[0017] where R.sup.10 is selected from H; C.sub.1-8-alkyl or
C.sub.3-8-cycloalkyl, in each case saturated or unsaturated,
branched or unbranched, singly or multiply substituted or
unsubstituted; aryl or heteroaryl, in each case singly or multiply
substituted or unsubstituted; or aryl, C.sub.3-8-cycloalkyl or
heteroaryl bound via C.sub.1-3-alkylene and in each case singly or
multiply substituted or unsubstituted;
[0018] where R.sup.9 is selected from C.sub.1-8-alkyl or
C.sub.3-8-cycloalkyl, in each case saturated or unsaturated,
branched or unbranched, singly or multiply substituted or
unsubstituted; aryl, heteroaryl, in each case unsubstituted or
singly or multiply substituted; aryl, C.sub.3-8-cycloalkyl or
heteroaryl bound via a saturated or unsaturated, branched or
unbranched, substituted or unsubstituted C.sub.1-4-alkyl group and
in each case unsubstituted or singly or multiply substituted;
[0019] R.sup.5 is selected from C.sub.3-8-cycloalkyl, aryl or
heteroaryl, in each case unsubstituted or singly or multiply
substituted; --CHR.sup.11R.sup.12, --CHR.sup.11--CH.sub.2R.sup.12,
--CHR.sup.11--CH.sub.2--CH.sub.2R.sup.12,
--CHR.sup.11--CH.sub.2--CH.sub.- 2--CH.sub.2R.sup.12,
--C(Y)R.sup.12, --C(Y)--CH.sub.2R.sup.12,
--C(Y)--CH.sub.2--CH.sub.2R.sup.12 or
--C(Y)--CH.sub.2--CH.sub.2--CH.sub.- 2R.sup.12
[0020] where Y=O, S or H.sub.2,
[0021] where R.sup.11 is selected from
[0022] H, C.sub.1-7-alkyl that is saturated or unsaturated,
branched or unbranched, singly or multiply substituted or
unsubstituted; or C(O)O--C.sub.1-6-alkyl that is saturated or
unsaturated, branched or unbranched, singly or multiply substituted
or unsubstituted;
[0023] and where R.sup.12 is selected from
[0024] H; C.sub.3-8-cycloalkyl, aryl or heteroaryl, in each case
unsubstituted or singly or multiply substituted,
[0025] or R.sup.4 and R.sup.5 together form a heterocycle with
between 3 and 8 atoms in the ring, which is saturated or
unsaturated; singly or multiply substituted or unsubstituted, and
which may optionally be condensed with further rings,
[0026] optionally in the form of their racemates, their pure
stereoisomers, in particular enantiomers or diastereomers, or in
the form of mixtures of the stereoisomers, in particular of the
enantiomers or diastereomers, in an arbitrary mixture ratio;
[0027] in the prepared form or in the form of their acids or bases
or in the form of their salts, in particular of the physiologically
compatible salts, or salts of physiologically compatible acids or
cations; or in the form of their solvates, in particular the
hydrates; for the production of a medicament and for the treatment
of diarrhea or irritable bowel diseases or for use as an
immunotherapeutic agent or as a peripheral analgesic, in particular
for the treatment of burn pains, pain in inflammation of soft
tissues, peripheral operation pain or inflammatory joint diseases,
in particular rheumatism.
[0028] The compounds used are outstanding peripherally active
.mu.-agonists without any effect on the central nervous system.
[0029] Preferably the compounds are not CNS-accessible and thus
have the desired peripheral selectivity. They are suitable as
antidiarrhea agents as well as for the treatment of other
gastrointestinal diseases that are associated with hypermotility
and hypersecretion. They may furthermore be employed as
peripherally active analgesics that are particularly effective in
treating burn pains, inflammation pain and in painful diseases of
the joints. Furthermore the substances are suitable as
immunotherapeutic agents. Their particular advantage is the lack of
any effect on the central nervous system. Accordingly the side
effects transmitted via CNS opiate receptors such as euphoria,
potential for addiction and dependence (including dependence on the
narcotic effect of the substance) and respiratory depression are
absent.
[0030] Within the context of the present invention alkyl and
cycloalkyl radicals are understood to denote saturated and
unsaturated (but not aromatic), branched, unbranched and cyclic
hydrocarbons, which may be unsubstituted or singly or multiply
substituted. In this connection C.sub.1-2-alkyl denotes C1- or
C2-alkyl, C.sub.1-3-alkyl denotes C1-, C2- or C3-alkyl,
C.sub.1-4-alkyl denotes C1-, C2-, C3- or C4-alkyl, C.sub.1-5-alkyl
denotes C1-, C2-, C3-, C4- or C5-alkyl, C.sub.1-6-alkyl denotes
C1-, C2-, C3-, C4-, C5- or C6-alkyl, C.sub.1-7-alkyl denotes C1-,
C2-, C3-, C4-, C5-, C6- or C7-alkyl, C.sub.1-8-alkyl denotes C1-,
C2-, C3-, C4-, C5-, C6-, C7- or C8-alkyl, C.sub.1-10-alkyl denotes
C1-, C2-, C3-, C4-, C5-, C6-, C7-, C8-, C9- or C10-alkyl and
C.sub.1-18-alkyl denotes C1-, C2-, C3-, C4-, C5-, C6-, C7-, C8-,
C9-, C10-, C11-, C12-, C13-, C14-, C15-, C16-, C17- or C18-alkyl.
Furthermore C.sub.3-4-cycloalkyl denotes C3- or C4-cycloalkyl,
C.sub.3-5-cycloalkyl denotes C3-, C4- or C5-cycloalkyl,
C.sub.3-6-cycloalkyl denotes C3-, C4-, C5- or C6-cycloalkyl,
C.sub.3-7-cycloalkyl denotes C3-, C4-, C5-, C6- or C7-cycloalkyl,
C.sub.3-8-cycloalkyl denotes C3-, C4-, C5-, C6, C7- or
C8-cycloalkyl, C.sub.4-5-cycloalkyl denotes C4- or C5-cycloalkyl,
C.sub.4-6-cycloalkyl denotes C4-, C5- or C6-cycloalkyl,
C.sub.4-7-cycloalkyl denotes C4-, C5-, C6- or C7-cycloalkyl,
C.sub.5-6-cycloalkyl denotes C5- or C6-cycloalkyl and
C.sub.5-7-cycloalkyl denotes C5-, C6- or C7-cycloalkyl. With regard
to cycloalkyl, the term also includes saturated cycloalkyls in
which 1 or 2 carbon atoms are replaced by a heteroatom, i.e. S, N
or O. The term cycloalkyl however also includes in particular
singly or multiply, preferably singly, unsaturated cycloalkyls
without a heteroatom in the ring provided that the cycloalkyl does
not form an aromatic system. Preferably the alkyl and cycloalkyl
radicals are methyl, ethyl, vinyl (ethenyl), propyl, allyl
(2-propenyl), 1-propinyl, methylethyl, butyl, 1-methylpropyl,
2-methylpropyl, 1,1-dimethylethyl, pentyl, 1,1-dimethylpropyl,
1,2-dimethylpropyl, 2,2-dimethylpropyl, hexyl, 1-methylpentyl,
cyclopropyl, 2-methylcyclopropyl, cyclopropylmethyl, cyclobutyl,
cyclopentyl, cyclopentyl-methyl, cyclohexyl, cycloheptyl,
cyclooctyl, but also adamantyl, CHF.sub.2, CF.sub.3 or CH.sub.2OH
as well as pyrazolinone, oxopyrazolinone, [1,4]dioxane or
dioxolane.
[0031] In connection with alkyl and cycloalkyl--unless specifically
defined otherwise--the term substituted within the context of the
present invention denotes the substitution (replacement) of at
least one (optionally also several) hydrogen atom(s) by F, Cl, Br,
I, NH.sub.2, SH or OH, in which "multiply substituted" or
"substituted" in the case of multiple substitution is understood to
mean that the substitution takes place on different atoms as well
as on the same atoms multiply with the same or different
substituents, for example triply on the same C atom as in the case
of CF.sub.3, or at different positions as in the case of
--CH(OH)--CH.dbd.CH--CHCl.sub.2. Particularly preferred
substituents in this connection are F, Cl and OH. With regard to
cycloalkyl, the hydrogen atom may also be replaced by
OC.sub.1-3-alkyl or C.sub.1-3-alkyl (in each case singly or
multiply substituted or unsubstituted), in particular by methyl,
ethyl, n-propyl, i-propyl, CF.sub.3, methoxy or ethoxy.
[0032] The term (CH.sub.2).sub.3-6 is understood to denote
--CH.sub.2--CH.sub.2--CH.sub.2--,
--CH.sub.2--CH.sub.2--CH.sub.2--CH.sub.- 2--,
--CH.sub.2--CH.sub.2--CH.sub.2--CH.sub.2--CH.sub.2-- and
--CH.sub.2--CH.sub.2--CH.sub.2--CH.sub.2--CH.sub.2--CH.sub.2--, the
term (CH.sub.2).sub.1-4 is understood to denote --CH.sub.2--,
--CH.sub.2--CH.sub.2--, --CH.sub.2--CH.sub.2--CH.sub.2-- and
--CH.sub.2--CH.sub.2--CH.sub.2--CH.sub.2--, and (CH.sub.2).sub.4-5
is understood to denote --CH.sub.2--CH.sub.2--CH.sub.2--CH.sub.2--
and --CH.sub.2--CH.sub.2--CH.sub.2--CH.sub.2--CH.sub.2--, etc.
[0033] An aryl radical is understood to denote ring systems with at
least one aromatic ring but without heteroatoms in even only one of
the rings. Examples include phenyl, naphthyl, fluoranthenyl,
fluorenyl, tetralinyl or indanyl, in particular 9H-fluorenyl or
anthracenyl radicals, which may be unsubstituted or singly or
multiply substituted. A heteroaryl radical is understood to denote
heterocyclic ring systems with at least one unsaturated ring, which
may contain one or more heteroatoms from the group comprising
nitrogen, oxygen and/or sulfur, and may also be singly or multiply
substituted. By way of example there may be mentioned from the
group of heteroaryls, furan, benzofuran, thiophene, benzothiophene,
pyrrole, pyridine, pyrimidine, pyrazine, quinoline, isoquinoline,
phthalazine, benzo[1,2,5]thiadiazole, benzothiazole, indole,
benzotriazole, benzodioxolane, benzodioxane, carbazole, indole and
quinazoline.
[0034] In connection with aryl and heteroaryl, the term substituted
is understood to denote the substitution of the aryl or heteroaryl
with R.sup.22, OR.sup.22, a halogen, preferably F and/or Cl, a
CF.sub.3, a CN, an NO.sub.2, an NR.sup.23R.sup.24, a
C.sub.1-6-alkyl (saturated), a C.sub.1-6-alkoxy, a
C.sub.3-8-cycloalkoxy, a C.sub.3-8-cycloalkyl or a
C.sub.2-6-alkylene.
[0035] In this connection the radical R.sup.22 denotes H, a
C.sub.1-10-alkyl radical, preferably a C.sub.1-6-alkyl radical, an
aryl or heteroaryl radical, or an aryl or heteroaryl radical bound
via C.sub.1-3-alkyl that is saturated or unsaturated, or bound via
a C.sub.1-3-alkylene group, wherein these aryl and heteroaryl
radicals may not themselves be substituted by aryl or heteroaryl
radicals,
[0036] the radicals R.sup.23 and R.sup.24, which are identical or
different, denote H, a C.sub.1-10-alkyl radical, preferably a
C.sub.1-6-alkyl radical, an aryl radical, a heteroaryl radical, or
an aryl or heteroaryl radical bound via C.sub.1-3-alkyl that is
saturated or unsaturated, or bound via a C.sub.1-3-alkylene group,
wherein these aryl and heteroaryl radicals may not themselves be
substituted by aryl or heteroaryl radicals,
[0037] or the radical R.sup.23 and R.sup.24 together denote
CH.sub.2CH.sub.2OCH.sub.2CH.sub.2,
CH.sub.2CH.sub.2NR.sup.25CH.sub.2CH.su- b.2 or (CH.sub.2).sub.3-6,
and
[0038] the radical R.sup.25 denotes H, a C.sub.1-10-alkyl radical,
preferably a C.sub.1-6-alkyl radical, an aryl or heteroaryl
radical, or denotes an aryl or heteroaryl radical bound via
C.sub.1-3-alkyl that is saturated or unsaturated, or bound via a
C.sub.1-3-alkylene group, wherein these aryl and heteroaryl
radicals may not themselves be substituted by aryl or heteroaryl
radicals.
[0039] The term salt is understood to denote any form of the active
substance according to the invention in which this adopts an ionic
form or is charged and is coupled with a counterion (a cation or
anion), or is present in solution. The term is also understood to
include complexes of the active substance with other molecules and
ions, in particular complexes that are complexed via ionic
interactions. In particular the term salt is understood (and this
is also a preferred embodiment of the present invention) to denote
physiologically compatible salts, in particular physiologically
compatible salts with cations or bases and physiologically
compatible salts with anions or acids or also a salt formed with a
physiologically compatible acid or with a physiologically
compatible cation.
[0040] The term physiologically compatible salt with anions or
acids is understood within the context of the present invention to
denote salts of at least one of the compounds according to the
invention--generally protonated, for example on the nitrogen
atom--as a cation with at least one anion, that are physiologically
compatible, especially when used in humans and/or mammals. In
particular the term is understood within the context of the present
invention to mean the salt formed with a physiologically compatible
acid, namely salts of the respective active substance with
inorganic or organic acids, which are physiologically compatible,
especially when used in humans and/or mammals. Examples of
physiologically compatible salts of specific acids are salts of the
following: hydrochloric acid, hydrobromic acid, sulfuric acid,
methanesulfonic acid, formic acid, acetic acid, oxalic acid,
succinic acid, malic acid, tartaric acid, mandelic acid, fumaric
acid, lactic acid, citric acid, glutamic acid,
1,1-dioxo-1,2-dihydro1.lambda..sup.6-be- nzo[d]isothiazol-3-one
(saccharinic acid), monomethylsebacic acid, 5-oxoproline,
hexane-1-sulfonic acid, nicotinic acid, 2-, 3- or 4-aminobenzoic
acid, 2,4,6-trimethylbenzoic acid, .alpha.-lipoic acid,
acetylglycine, acetylsalicylic acid, hippuric acid and/or aspartic
acid. The hydrochloride salt is particularly preferred.
[0041] The term salt formed with a physiologically compatible acid
is understood within the context of the present invention to denote
salts of the respective active substance with inorganic or organic
acids that are physiologically compatible, especially when used in
humans and/or mammals. The hydrochloride is particularly preferred.
Examples of physiologically compatible acids include: hydrochloric
acid, hydrobromic acid, sulfuric acid, methanesulfonic acid, formic
acid, acetic acid, oxalic acid, succinic acid, tartaric acid,
mandelic acid, fumaric acid, lactic acid, citric acid, glutamic
acid, 1,1-dioxo-1,2-dihydro1.lambda..s-
up.6-benzo[d]isothiazol-3-one (saccharinic acid), monomethylsebacic
acid, 5-oxoproline, hexane-1-sulfonic acid, nicotinic acid, 2-, 3-
or 4-aminobenzoic acid, 2,4,6-trimethylbenzoic acid, .alpha.-lipoic
acid, acetylglycine, acetylsalicylic acid, hippuric acid and/or
aspartic acid.
[0042] The term physiologically compatible salt with cations or
bases is understood within the context of the present invention to
denote salts of at least one of the compounds according to the
invention--generally a (deprotonated) acid--as anion with at least
one, preferably inorganic, cation, which are physiologically
compatible, especially when used in humans and/or mammals.
Particularly preferred are the salts of alkali and alkaline earth
metals, but also NH.sub.4.sup.+, but in particular (mono) or (di)
sodium, (mono) or (di) potassium, magnesium or calcium salts.
[0043] The term salt formed with a physiologically compatible
cation is understood within the context of the present invention to
denote salts of at least one of the respective compounds as anion
with at least one inorganic cation, which are physiologically
compatible, especially when used in humans and/or mammals.
Particularly preferred are salts of alkali and alkaline earth
metals, but also salts of NH.sub.4.sup.+, and in particular (mono)
or (di) sodium, (mono) or (di) potassium, magnesium or calcium
salts.
[0044] The medicaments contain in addition to at least one
substituted cyclohexane-1,4-diamine compound, optionally suitable
additives and/or auxiliary substances, thus also carrier materials,
fillers, solvents, diluents, colourants and/or binders, and may be
administered as liquid medicament forms in the form of injection
solutions, droplets or juices, as semi-solid medicament forms in
the form of granules, tablets, pellets, patches, capsules, plasters
or aerosols. The choice of the auxiliary substances etc., as well
as the amounts thereof to be used depend on whether the medicament
is to be administered orally, parenterally, intravenously,
intraperitoneally, intradermally, intramuscularly, intranasally,
buccally, rectally or topically, for example to the skin, the
mucous membranes or the eyes. For oral application preparations in
the form of tablets, sugar-coated pills, capsules, granules,
droplets, juices and syrups are suitable, while for parenteral,
topical and inhalative application solutions, suspensions, readily
reconstitutable dry preparations as well as sprays are suitable.
Substituted cyclohexane-1,4-diamine compounds according to the
invention in a depot form, in dissolved form or in a plaster,
optionally with the addition of agents promoting penetration of the
skin, are suitable percutaneous application preparations. Orally or
percutaneously usable preparation forms may provide for the delayed
release of the substituted cyclohexane-1,4-diamine compounds
according to the invention. In principle other active substances
known to the person skilled in the art may be added to the
medicaments according to the invention.
[0045] The amount of active substance to be administered to the
patient varies depending on the patient's weight, type of
application, medical indication and the severity of the disease.
Normally 0.005 to 1000 mg/kg, preferably 0.05 to 5 mg/kg of at
least one substituted cyclohexane-1,4-diamine compound are
administered.
[0046] In the uses according to the invention it may be preferred
if, in the compound according to formula I that is used, R.sup.1
and R.sup.2 are not both H.
[0047] Likewise and in addition it may be preferred if in formula
I
[0048] R.sup.1 and R.sup.2 independently of one another are
selected from H; C.sub.1-8-alkyl that is saturated or unsaturated,
branched or unbranched, singly or multiply substituted or
unsubstituted;
[0049] or the radicals R.sup.1 and R.sup.2 together form a ring and
denote CH.sub.2CH.sub.2OCH.sub.2CH.sub.2,
CH.sub.2CH.sub.2NR.sup.6CH.sub.2CH.sub- .2 or
(CH.sub.2).sub.3-6,
[0050] where R.sup.6 is selected from H; C.sub.1-8-alkyl that is
saturated or unsaturated, branched or unbranched, singly or
multiply substituted or unsubstituted,
[0051] preferably
[0052] R.sup.1 and R.sup.2 independently of one another are
selected from H; C.sub.1-4-alkyl that is saturated or unsaturated,
branched or unbranched, singly or multiply substituted or
unsubstituted;
[0053] or the radicals R.sup.1 and R.sup.2 together form a ring and
denote (CH.sub.2).sub.4-5;
[0054] in particular
[0055] R.sup.1 and R.sup.2 independently of one another are
selected from methyl or ethyl or the radicals R.sup.1 and R.sup.2
together form a ring and denote (CH.sub.2).sub.5.
[0056] In one of the uses mentioned hereinbefore it may be
preferred if in formula I
[0057] R.sup.3 is selected from C.sub.3-8-cycloalkyl, aryl or
heteroaryl, in each case unsubstituted or singly or multiply
substituted; aryl, C.sub.3-8-cycloalkyl or heteroaryl bound via a
saturated or unsaturated, unbranched, substituted or unsubstituted
C.sub.1-2-alkyl group, and in each case unsubstituted or singly or
multiply substituted;
[0058] preferably
[0059] R.sup.3 is selected from C.sub.5-6-cycloalkyl, phenyl,
naphthyl, anthracenyl, thiophenyl, benzothiophenyl, furyl,
benzofuranyl, benzodioxolanyl, indolyl, indanyl, benzodioxanyl,
pyrrolyl, pyridyl, pyrimidyl or pyrazinyl, in each case
unsubstituted or singly or multiply substituted;
C.sub.5-6-cycloalkyl, phenyl, naphthyl, anthracenyl, thiophenyl,
benzothiophenyl, pyridyl, furyl, benzofuranyl, benzodioxolanyl,
indolyl, indanyl, benzodioxanyl, pyrrolyl, pyrimidyl or pyrazinyl
bound via a saturated, unbranched C.sub.1-2-alkyl group and in each
case unsubstituted or singly or multiply substituted;
[0060] in particular
[0061] R.sup.3 is selected from phenyl, furyl, thiophenyl,
cyclohexanyl, naphthyl, benzofuranyl, indolyl, indanyl,
benzodioxanyl, benzodioxolanyl, pyridyl, pyrrolyl, pyrimidyl,
pyrazinyl or benzothiophenyl, in each case unsubstituted or singly
or multiply substituted; phenyl, furyl or thiophenyl bound via a
saturated, unbranched C.sub.1-2-alkyl group and in each case
unsubstituted or singly or multiply substituted.
[0062] In one of the uses mentioned hereinbefore it may be
preferred if in formula I R.sup.4 is H.
[0063] Likewise, in one of the uses mentioned hereinbefore it may
be preferred if in formula I
[0064] R.sup.4 is selected from H, C(X)R.sup.7,
C(X)NR.sup.7R.sup.8, C(X)OR.sup.9, C(X)SR.sup.9 or
S(O.sub.2)R.sup.9 where X=O or S,
[0065] preferably
[0066] R.sup.4 is selected from H, C(X)R.sup.7, C(X)NR.sup.7R.sup.8
or C(X)OR.sup.9 where X=O,
[0067] in particular
[0068] R.sup.4 is selected from H or C(O)R.sup.7; preferably where
R.sup.7 is selected from
[0069] H; or C.sub.1-8-alkyl that is saturated or unsaturated,
branched or unbranched, singly or multiply substituted or
unsubstituted;
[0070] preferably
[0071] H; or C.sub.1-3-alkyl that is saturated, unsubstituted,
branched or unbranched;
[0072] in particular CH.sub.3.
[0073] In one of the uses mentioned hereinbefore it may be
preferred if in formula I
[0074] R.sup.4 and R.sup.5 together form a heterocycle with between
3 and 8 atoms in the ring, which is saturated or unsaturated;
singly or multiply substituted or unsubstituted, preferably with
between 5 and 7 atoms in the ring, of which apart from the
obligatory N, 0 to 1 further heteroatoms selected from N, S or O
are in the ring;
[0075] wherein the heterocycle formed from R.sup.4 and R.sup.5 may
optionally be condensed with further rings,
[0076] preferably with aromatic and/or heteroaromatic rings,
wherein these may be condensed with further aromatic and/or
heteroaromatic rings,
[0077] in particular the heterocycle formed from R.sup.4 and
R.sup.5 is condensed with one or two further rings, preferably the
heterocycle formed from R.sup.4 and R.sup.5 is condensed with two
further rings in such a way that R.sup.4 and R.sup.5 together
denote 2
[0078] In one of the uses mentioned hereinbefore it may be
preferred if in formula I
[0079] R.sup.4 is selected from H, C.sub.1-8-alkyl that is
saturated or unsaturated, branched or unbranched, singly or
multiply substituted or unsubstituted,
[0080] preferably
[0081] H, C.sub.1-6-alkyl that is saturated or unsaturated,
branched or unbranched, singly or multiply substituted or
unsubstituted,
[0082] in particular
[0083] H, C.sub.1-3-alkyl that is saturated, unbranched and
unsubstituted.
[0084] In one of the uses mentioned hereinbefore it may be
preferred if in formula I
[0085] R.sup.5 is selected from C.sub.3-8-cycloalkyl, aryl or
heteroaryl, in each case unsubstituted or singly or multiply
substituted;
[0086] preferably
[0087] R.sup.5 is selected from cyclobutyl, cyclopropyl,
cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, anthracenyl,
indolyl, naphthyl, benzofuranyl, benzothiophenyl, indanyl,
benzodioxanyl, benzodioxolanyl, acenaphthyl, carbazolyl, phenyl,
thiophenyl, furyl, pyridyl, pyrrolyl, pyrazinyl or pyrimidyl,
fluorenyl, fluoranthenyl, benzothiazolyl, benzotriazolyl or
benzo[1,2,5]thiazolyl or 1,2-dihydroacenaphthenyl, pyridinyl,
furanyl, benzofuranyl, pyrazolinonyl, oxopyrazolinonyl, dioxolanyl,
adamantyl, pyrimidinyl, quinolinyl, isoquinolinyl, phthalazinyl or
quinazolinyl, in each case unsubstituted or singly or multiply
substituted;
[0088] in particular
[0089] R.sup.5 is selected from cyclopentyl, cyclohexyl,
cycloheptyl, cyclooctyl, anthracenyl, indolyl, naphthyl,
benzofuranyl, benzothiophenyl, indanyl, benzodioxanyl,
benzodioxolanyl, acenaphthyl, carbazolyl, phenyl, thiophenyl,
furyl, pyridyl, pyrrolyl, pyrazinyl or pyrimidyl, in each case
unsubstituted or singly or multiply substituted.
[0090] Likewise, in one of the uses mentioned hereinbefore it may
be preferred if in formula I
[0091] R.sup.5 is selected from --CHR.sup.11R.sup.12,
--CHR.sup.11--CH.sub.2R.sup.12,
--CHR.sup.11--CH.sub.2--CH.sub.2R.sup.12,
--CHR.sup.11--CH.sub.2--CH.sub.2--CH.sub.2R.sup.12, --C(Y)R.sup.12,
--C(Y)--CH.sub.2R.sup.12, --C(Y)--CH.sub.2--CH.sub.2R.sup.12 or
--C(Y)--CH.sub.2--CH.sub.2--CH.sub.2R.sup.12
[0092] where Y=O, S or H.sub.2,
[0093] preferably
[0094] R.sup.5 is selected from --CHR.sup.11R.sup.12,
--CHR.sup.11--CH.sub.2R.sup.12,
--CHR.sup.11--CH.sub.2--CH.sub.2R.sup.12, --C(Y)R.sup.12,
--C(Y)--CH.sub.2R.sup.12 or --C(Y)--CH.sub.2--CH.sub.2R.s-
up.12
[0095] where Y=O or S,
[0096] in particular
[0097] R.sup.5 is selected from --CHR.sup.11R.sup.12,
--CHR.sup.11--CH.sub.2R.sup.12,
--CHR.sup.11--CH.sub.2--CH.sub.2R.sup.12, --C(Y)R.sup.12 or
--C(Y)--CH.sub.2R.sup.12
[0098] where Y=O.
[0099] With regard to the preceding embodiment it is preferred if
in the substituted cyclohexane-1,4-diamine compounds according to
formula I that are used
[0100] R.sup.11 is selected from
[0101] H, C.sub.1-4-alkyl that is saturated or unsaturated,
branched or unbranched, singly or multiply substituted or
unsubstituted; or C(O)O--C.sub.1-4-alkyl that is saturated or
unsaturated, branched or unbranched, singly or multiply substituted
or unsubstituted;
[0102] preferably
[0103] H, C.sub.1-4-alkyl that is saturated or unsaturated,
branched or unbranched, singly or multiply substituted or
unsubstituted; or C(O)O--C.sub.1-2-alkyl that is saturated,
unbranched, singly or multiply substituted or unsubstituted;
[0104] in particular
[0105] H, CH.sub.3, C.sub.2H.sub.5 and C(O)O--CH.sub.3;
[0106] and/or, if in the substituted cyclohexane-1,4-diamine
compounds according to formula I that are used
[0107] R.sup.12 is selected from C.sub.3-8-cycloalkyl, aryl or
heteroaryl, in each case unsubstituted or singly or multiply
substituted;
[0108] preferably
[0109] R.sup.12 is selected from cyclobutyl, cyclopropyl,
cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, anthracenyl,
indolyl, naphthyl, benzofuranyl, benzothiophenyl, indanyl,
benzodioxanyl, benzodioxolanyl, acenaphthyl, carbazolyl, phenyl,
thiophenyl, furyl, pyridyl, pyrrolyl, pyrazinyl or pyrimidyl,
fluorenyl, fluoranthenyl, benzothiazolyl, benzotriazolyl or
benzo[1,2,5]thiazolyl or 1,2-dihydroacenaphthenyl, pyridinyl,
furanyl, benzofuranyl, pyrazolinonyl, oxopyrazolinonyl, dioxolanyl,
adamantyl, pyrimidinyl, quinolinyl, isoquinolinyl, phthalazinyl or
quinazolinyl, in each case unsubstituted or singly or multiply
substituted;
[0110] in particular
[0111] R.sup.12 is selected from cyclopentyl, cyclohexyl,
cycloheptyl, cyclooctyl, anthracenyl, indolyl, naphthyl,
benzofuranyl, benzothiophenyl, indanyl, benzodioxanyl,
benzodioxolanyl, acenaphthyl, carbazolyl, phenyl, thiophenyl,
furyl, pyridyl, pyrrolyl, pyrazinyl or pyrimidyl, in each case
unsubstituted or singly or multiply substituted.
[0112] Furthermore it is particularly preferred to use according to
the invention substituted cyclohexane-1,4-diamine compounds
selected from the following group:
[0113] N'-benzyl-N,N-dimethyl-1-phenylcyclohexane-1,4-diamine
hydrochloride, non-polar diastereomer
[0114] N'-benzyl-N,N-dimethyl-1-phenylcyclohexane-1,4-diamine
hydrochloride, polar diastereomer
[0115] 1,N'-dibenzyl-N,N-dimethylcyclohexane-1,4-diamine
hydrochloride, non-polar diastereomer
[0116] 1,N'-dibenzyl-N,N-dimethylcyclohexane-1,4-diamine
hydrochloride, polar diastereomer
[0117] N-(4-benzyl-4-dimethylaminocyclohexyl)-N-propylbenzamide
hydrochloride
[0118] N,N-dimethyl-1-phenyl-N'-propylcyclohexane-1,4-diamine
hydrochloride, non-polar diastereomer
[0119] N-(4-dimethylamino-4-phenylcyclohexyl)-N-propylbenzamide
hydrochloride, non-polar diastereomer
[0120] N-(4-dimethylamino-4-phenylcyclohexyl)-N-propylbenzamide
hydrochloride, polar diastereomer
[0121] 1,N'-dibenzyl-N,N,N'-trimethylcyclohexane-1,4-diamine
hydrochloride, non-polar diastereomer
[0122] 1,N'-dibenzyl-N,N,N'-trimethylcyclohexane-1,4-diamine
hydrochloride, polar diastereomer
[0123] N-(4-benzyl-4-dimethylaminocyclohexyl)-N-methylbenzamide
hydrochloride, polar diastereomer
[0124] N-(4-benzyl-4-dimethylaminocyclohexyl)-N-ethylbenzamide
hydrochloride, polar diastereomer
[0125]
1-benzyl-N'-(1H-indol-3-ylmethyl)-N,N-dimethylcyclohexane-1,4-diami-
ne dihydrochloride
[0126]
1-benzyl-N'-[2-(1H-indol-3-yl)-1-methylethyl]-N,N-dimethylcyclohexa-
ne-1,4-diamine, cis/trans mixture
[0127] 1-benzyl-N'-indan-5-yl-N,N-dimethylcyclohexane-1,4-diamine
hydrochloride
[0128] 1-benzyl-N'-indan-1-yl-N,N-dimethylcyclohexane-1,4-diamine
dihydrochloride, cis/trans mixture
[0129]
N'-indan-1-yl-N,N-dimethyl-1-phenylcyclohexane-1,4-diamine
[0130]
N'-(1H-indol-5-yl)-N,N-dimethyl-1-phenylcyclohexane-1,4-diamine
[0131]
N'-(1H-indol-3-ylmethyl)-N,N-dimethyl-1-phenylcyclohexane-1,4-diami-
ne, cis/trans mixture
[0132]
N'-(1H-indol-3-ylmethyl)-N,N-dimethyl-1-phenylcyclohexane-1,4-diami-
ne, non-polar diastereomer
[0133]
N'-[2-(1H-indol-3-yl)-ethyl]-N,N-dimethyl-1-phenylcyclohexane-1,4-d-
iamine, non-polar diastereomer
[0134]
N'-[2-(1H-indol-3-yl)-ethyl]-N,N-dimethyl-1-phenylcyclohexane-1,4-d-
iamine, cis/trans mixture
[0135] N'-indan-5-yl-N,N-dimethyl-1-phenylcyclohexane-1,4-diamine,
non-polar diastereomer
[0136]
N'-[2-(1H-indol-3-yl)-1-methylethyl]-N,N-dimethyl-1-phenylcyclohexa-
ne-1,4-diamine, non-polar diastereomer
[0137]
N'-[2-(1H-indol-3-yl)-1-methylethyl]-N,N-dimethyl-1-phenylcyclohexa-
ne-1,4-diamine, cis/trans mixture
[0138]
N'-[2-(5-benzyloxy-1H-indol-3-yl)-ethyl]-N,N-dimethyl-1-phenylcyclo-
hexane-1,4-diamine, cis/trans mixture
[0139]
N'-(9H-fluoren-1-yl)-N,N-dimethyl-1-phenylcyclohexane-1,4-diamine
dihydrochloride
[0140] N'-indan-2-yl-N,N-dimethyl-1-phenylcyclohexane-1,4-diamine
dihydrochloride, cis/trans mixture
[0141]
N'-(9H-fluoren-9-yl)-N,N-dimethyl-1-phenylcyclohexane-1,4-diamine
dihydrochloride, cis/trans mixture
[0142] 1-benzyl-N'-(9H-f
fluoren-9-yl)-N,N-dimethylcyclohexane-1,4-diamine
[0143]
1-benzyl-N'-(1H-indol-3-ylmethyl)-N,N-dimethylcyclohexane-1,4-diami-
ne, cis/trans mixture
[0144]
N,N-dimethyl-N'-(1-methyl-1H-indol-3-ylmethyl)-1-phenylcyclohexane--
1,4-diamine, cis/trans mixture
[0145]
N,N-dimethyl-N'-(1-methyl-1H-indol-3-ylmethyl)-1-phenylcyclohexane--
1,4-diamine, polar diastereomer
[0146]
N'-(2-benzo[b]thiophen-3-yl-ethyl)-N,N-dimethyl-1-phenylcyclohexane-
-1,4-diamine dihydrochloride, cis/trans mixture
[0147]
N'-(2-benzo[b]thiophen-3-yl-ethyl)-1-benzyl-N,N-dimethylcyclohexane-
-1,4-diamine dihydrochloride, cis/trans mixture
[0148]
N'-acenaphthen-1-yl-N,N-dimethyl-1-phenylcyclohexane-1,4-diamine
dihydrochloride, polar diastereomer
[0149]
N'-acenaphthen-1-yl-N,N-dimethyl-1-phenylcyclohexane-1,4-diamine
dihydrochloride, non-polar diastereomer
[0150]
N'-benzo[b]thiophen-5-yl-1-benzyl-N,N-dimethylcyclohexane-1,4-diami-
ne dihydrochloride, non-polar diastereomer
[0151]
N'-benzo[b]thiophen-5-yl-N,N-dimethyl-1-phenylcyclohexane-1,4-diami-
ne hydrochloride, non-polar diastereomer
[0152]
N'-benzothiazol-6-yl-N,N-dimethyl-1-phenylcyclohexane-1,4-diamine
dihydrochloride, non-polar diastereomer
[0153]
N'-benzo[1,2,5]thiadiazol-4-yl-N,N-dimethyl-1-phenylcyclohexane-1,4-
-diamine dihydrochloride, polar diastereomer
[0154]
N'-[2-(1H-indol-3-yl)-1-methylethyl]-N,N-dimethyl-1-phenylcyclohexa-
ne-1,4-diamine dihydrochloride, non-polar diastereomer
[0155]
N'-adamantan-2-yl-N,N-dimethyl-1-phenylcyclohexane-1,4-diamine
dihydrochloride
[0156]
N'-(9-ethyl-9H-carbazol-3-yl)-N,N-dimethyl-1-phenylcyclohexane-1,4--
diamine dihydrochloride, non-polar diastereomer
[0157]
N'-(3H-benzotriazol-5-yl)-N,N-dimethyl-1-phenylcyclohexane-1,4-diam-
ine hydrochloride, non-polar diastereomer
[0158]
N'-(3H-benzotriazol-5-yl)-N,N-dimethyl-1-phenylcyclohexane-1,4-diam-
ine hydrochloride, polar diastereomer
[0159]
N'-(9H-fluoren-9-yl)-N,N-dimethyl-1-thiophen-2-yl-cyclohexane-1,4-d-
iamine dihydrochloride, cis/trans mixture
[0160] N'-cyclooctyl-N,N-dimethyl-1-phenylcyclohexane-1,4-diamine
dihydrochloride
[0161]
N'-(1H-indol-3-ylmethyl)-N,N-dimethyl-1-phenylcyclohexane-1,4-diami-
ne dihydrochloride, non-polar diastereomer
[0162]
N'-(1H-indol-3-ylmethyl)-N,N-dimethyl-1-phenylcyclohexane-1,4-diami-
ne dihydrochloride, polar diastereomer
[0163]
N'-benzo[b]thiophen-3-ylmethyl-N,N-dimethyl-1-phenylcyclohexane-1,4-
-diamine dihydrochloride, non-polar diastereomer
[0164]
N'-benzo[b]thiophen-3-ylmethyl-N,N-dimethyl-1-phenylcyclohexane-1,4-
-diamine dihydrochloride, polar diastereomer
[0165]
N'-anthracen-2-yl-N,N-dimethyl-1-phenylcyclohexane-1,4-diamine
hydrochloride, non-polar diastereomer
[0166]
N'-benzo[b]thiophen-3-ylmethyl-1-benzyl-N,N-dimethylcyclohexane-1,4-
-diamine dihydrochloride, non-polar diastereomer
[0167]
N'-benzo[b]thiophen-3-ylmethyl-1-benzyl-N,N-dimethylcyclohexane-1,4-
-diamine dihydrochloride, polar diastereomer
[0168]
N'-[2-(1H-indol-3-yl)-ethyl]-N,N-dimethyl-1-naphthalen-2-yl-cyclohe-
xane-1,4-diamine dihydrochloride, non-polar diastereomer
[0169]
N'-[2-(1H-indol-3-yl)-ethyl]-N,N-dimethyl-1-phenylcyclohexane-1,4-d-
iamine dihydrochloride, non-polar diastereomer
[0170]
N'-[2-(1H-indol-3-yl)-ethyl]-N,N-dimethyl-1-phenylcyclohexane-1,4-d-
iamine dihydrochloride, polar diastereomer
[0171]
N'-[2-(1H-indol-3-yl)-1-methylethyl]-N,N-dimethyl-1-phenylcyclohexa-
ne-1,4-diamine dihydrochloride, polar diastereomer
[0172] Methyl
2-(4-dimethylamino-4-phenylcyclohexylamino)-3-(1H-indol-3-yl-
)-propionate dihydrochloride, non-polar diastereomer
[0173] Methyl
2-(4-dimethylamino-4-phenylcyclohexylamino)-3-(1H-indol-3-yl-
)-propionate dihydrochloride, polar diastereomer
[0174]
N'-[2-(1H-indol-3-yl)-1-methylethyl]-N,N-dimethyl-1-naphthalen-2-yl-
-cyclohexane-1,4-diamine dihydrochloride, non-polar
diastereomer
[0175]
N'-benzo[1,3]dioxol-5-ylmethyl-N,N-dimethyl-1-phenylcyclohexane-1,4-
-diamine dihydrochloride, cis/trans mixture
[0176]
N'-[2-(6-fluoro-1H-indol-3-yl)-ethyl]-N,N-dimethyl-1-phenylcyclohex-
ane-1,4-diamine dihydrochloride, non-polar diastereomer
[0177]
N'-[2-(6-fluoro-1H-indol-3-yl)-ethyl]-N,N-dimethyl-1-phenylcyclohex-
ane-1,4-diamine dihydrochloride, polar diastereomer
[0178]
N'-[2-(1H-indol-3-yl)-ethyl]-N,N,N'-trimethyl-1-phenylcyclohexane-1-
,4-diamine dihydrochloride, non-polar diastereomer
[0179]
N'-[2-(1H-indol-3-yl)-ethyl]-N,N,N'-trimethyl-1-phenylcyclohexane-1-
,4-diamine dihydrochloride, polar diastereomer
[0180]
N,N-dimethyl-N'-[2-(7-methyl-1H-indol-3-yl)-ethyl]-1-phenylcyclohex-
ane-1,4-diamine dihydrochloride, non-polar diastereomer
[0181]
N,N-dimethyl-N'-[2-(7-methyl-1H-indol-3-yl)-ethyl]-1-phenylcyclohex-
ane-1,4-diamine dihydrochloride, polar diastereomer
[0182]
N'-[2-(5-fluoro-1H-indol-3-yl)-ethyl]-N,N-dimethyl-1-phenylcyclohex-
ane-1,4-diamine dihydrochloride, non-polar diastereomer
[0183]
N'-[2-(5-fluoro-1H-indol-3-yl)-ethyl]-N,N-dimethyl-1-phenylcyclohex-
ane-1,4-diamine dihydrochloride, polar diastereomer
[0184]
N'-acenaphthen-5-ylmethyl-N,N-dimethyl-1-phenylcyclohexane-1,4-diam-
ine dihydrochloride, non-polar diastereomer
[0185]
N'-[2-(1H-indol-3-yl)-1-methylethyl]-N,N-dimethyl-1-thiophen-2-yl-c-
yclohexane-1,4-diamine dihydrochloride, non-polar diastereomer
[0186]
N'-[2-(1H-indol-3-yl)-1-methylethyl]-N,N-dimethyl-1-thiophen-2-yl-c-
yclohexane-1,4-diamine dihydrochloride, cis/trans mixture
[0187]
N'-[2-(7-benzyloxy-1H-indol-3-yl)-ethyl]-N,N-dimethyl-1-phenylcyclo-
hexane-1,4-diamine dihydrochloride, non-polar diastereomer
[0188]
N'-cyclooctyl-N,N-dimethyl-1-thiophen-2-yl-cyclohexane-1,4-diamine
dihydrochloride, non-polar diastereomer
[0189]
N'-adamantan-2-yl-N,N-dimethyl-1-thiophen-2-yl-cyclohexane-1,4-diam-
ine dihydrochloride, non-polar diastereomer
[0190]
3-[2-(4-dimethylamino-4-phenylcyclohexylamino)-ethyl]-1H-indol-5-ol
dihydrochloride, non-polar diastereomer
[0191]
3-[2-(4-dimethylamino-4-phenylcyclohexylamino)-ethyl]-1H-indol-5-ol
dihydrochloride, polar diastereomer
[0192]
N'-[2-(5-methoxy-1H-indol-3-yl)-ethyl]-N,N-dimethyl-1-phenylcyclohe-
xane-1,4-diamine dihydrochloride, non-polar diastereomer
[0193]
N'-[2-(5-methoxy-1H-indol-3-yl)-ethyl]-N,N-dimethyl-1-phenylcyclohe-
xane-1,4-diamine dihydrochloride, polar diastereomer
[0194]
N,N-dimethyl-N'-[2-(5-methyl-1H-indol-3-yl)-ethyl]-1-phenylcyclohex-
ane-1,4-diamine dihydrochloride, non-polar diastereomer
[0195]
N,N-dimethyl-N'-[2-(5-methyl-1H-indol-3-yl)-ethyl]-1-phenylcyclohex-
ane-1,4-diamine dihydrochloride, polar diastereomer
[0196]
Dimethyl-[1-phenyl-4-(1,3,4,9-tetrahydro-b-carbolin-2-yl)-cyclohexy-
l]-amine dihydrochloride
[0197]
N-(4-dimethylamino-4-phenylcyclohexyl)-N-[2-(4-fluorophenyl)-ethyl]-
-acetamide hydrochloride, non-polar diastereomer
[0198]
2-(4-dimethylamino-4-phenylcyclohexylamino)-3-(5-fluoro-1H-indol-3--
yl)-propionic acid methyl ester dihydrochloride, non-polar
diastereomer
[0199]
N-(4-dimethylamino-4-phenylcyclohexyl)-N-(3-phenylpropyl)-acetamide
hydrochloride, non-polar diastereomer
[0200]
2-(4-dimethylamino-4-phenylcyclohexylamino)-3-(6-fluoro-1H-indol-3--
yl)-propionic acid methyl ester dihydrochloride, non-polar
diastereomer
[0201]
N-(4-dimethylamino-4-phenylcyclohexyl)-2-(1H-indol-3-yl)-acetamide
hydrochloride, polar diastereomer
[0202]
2-(4-dimethylamino-4-thiophen-2-yl-cyclohexylamino)-3-(1H-indol-3-y-
l)-propionic acid methyl ester dihydrochloride, non-polar
diastereomer
[0203]
N-(4-dimethylamino-4-phenylcyclohexyl)-2-(5-methoxy-1H-indol-3-yl)--
acetamide hydrochloride, non-polar diastereomer
[0204]
N,N-dimethyl-1-phenyl-N'-(2-pyridin-4-yl-ethyl)-cyclohexane-1,4-dia-
mine trihydrochloride,
[0205]
N,N-dimethyl-1-phenyl-N'-(2-pyridin-2-yl-ethyl)-cyclohexane-1,4-dia-
mine dihydrochloride, non-polar diastereomer
[0206]
N-(4-dimethylamino-4-pyridin-2-yl-cyclohexyl)-N-[2-(1H-indol-3-yl)--
ethyl]-acetamide dihydrochloride, non-polar diastereomer
[0207]
N'-[2-(1H-indol-3-yl)-ethyl]-N,N-dimethyl-1-pyridin-2-yl-cyclohexan-
e-1,4-diamine trihydrochloride, non-polar diastereomer
[0208]
N'-[2-(1H-indol-3-yl)-ethyl]-N,N-dimethyl-1-pyridin-2-yl-cyclohexan-
e-1,4-diamine trihydrochloride, polar diastereomer
[0209]
(S)-2-(4-dimethylamino-4-pyridin-2-yl-cyclohexylamino)-3-(1H-indol--
3-yl)-propionic acid methyl ester trihydrochloride, non-polar
diastereomer
[0210]
(S)-2-(4-dimethylamino-4-pyridin-2-yl-cyclohexylamino)-3-(1H-indol--
3-yl)-propionic acid methyl ester trihydrochloride, polar
diastereomer
[0211]
(S)-2-(4-dimethylamino-4-pyridin-2-yl-cyclohexylamino)-3-(1H-indol--
3-yl)-propionic acid dihydrochloride, non-polar diastereomer
[0212] in particular
[0213] potassium
(S)-2-(4-dimethylamino-4-phenylcyclohexylamino)-3-(1H-ind-
ol-3-yl)-propionate, non-polar diastereomer
[0214] potassium
rac-2-(4-dimethylamino-4-phenylcyclohexylamino)-3-(5-fluo-
ro-1H-indol-3-yl)-propionate, non-polar diastereomer
[0215] potassium
rac-2-(4-dimethylamino-4-phenylcyclohexylamino)-3-(6-fluo-
ro-1H-indol-3-yl)-propionate, non-polar diastereomer
[0216] potassium
(S)-2-(4-dimethylamino-4-thiophen-2-yl-cyclohexylamino)-3-
-(1H-indol-3-yl)-propionate, non-polar diastereomer
[0217]
(S)-2-(4-dimethylamino-4-thiophen-2-yl-cyclohexylamino)-3-(1H-indol-
-3-yl)-propionic acid hydrochloride, polar diastereomer
[0218]
(S)-2-(4-dimethylamino-4-phenylcyclohexylamino)-3-phenylpropionic
acid hydrochloride, non-polar diastereomer
[0219] potassium
rac-2-(4-dimethylamino-4-phenylcyclohexylamino)-4-phenylb- utyrate,
non-polar diastereomer
[0220]
rac-2-(4-dimethylamino-4-phenylcyclohexylamino)-4-phenylbutyric
acid hydrochloride, polar diastereomer
[0221]
(R)-2-(4-dimethylamino-4-phenylcyclohexylamino)-3-(1H-indol-3-yl)-p-
ropionic acid hydrochloride, non-polar diastereomer
[0222]
(R)-2-(4-dimethylamino-4-phenylcyclohexylamino)-3-phenylpropionic
acid hydrochloride, non-polar diastereomer
[0223]
rac-2-(4-dimethylamino-4-phenylcyclohexylamino)-3-(3-hydroxyphenyl)-
-propionic acid hydrochloride
[0224] optionally also in the form of their racemates, in the form
of the aforementioned or other pure stereoisomers, in particular
enantiomers or diastereomers, or in the form of mixtures of the
stereoisomers, in particular enantiomers or diastereomers, in an
arbitrary mixture ratio; optionally also in the form of the acids
or bases or in the form of other salts, in particular
physiologically compatible salts, or salts of physiologically
compatible acids or cations; or in the form of their solvates, in
particular hydrates.
[0225] In this connection, in one of the uses mentioned
hereinbefore it may be preferred if a substituted
cyclohexane-1,4-diamine compound that is employed is present as
pure diastereomer and/or enantiomer, as racemate or as a
non-equimolar or equimolar mixture of the diastereomers and/or
enantiomers.
[0226] Particularly suitable is the use of compounds that do not
have an effect on the central nervous system, in particular those
compounds that in a tail flick test in mice (according to Example
106) do not exhibit any analgesic effect at a dose of 10.0 mg/kg,
although they have an affinity in the .mu.molar to sub-.mu.molar
range for the .mu.-opioid receptor.
[0227] Suitable compounds may include, for example, those
cyclohexyl-1,4-diamine compounds in which both amino groups have
basic properties and are thus protonated under physiological
conditions, with the exception of .alpha.-aminobutyric acid ester
compounds.
[0228] Suitable compounds also include, for example, those
cyclohexyl-1,4-diamine compounds that are unesterified carboxylic
acids or that have a free carboxyl group.
[0229] The invention also provides a process for the treatment, in
particular in one of the aforementioned medical indications, of a
non-human mammal or human that requires a treatment for diarrhea or
irritable bowel diseases or a treatment with an immunotherapeutic
agent or peripheral analgesic, in particular for the treatment of
burn pains, pain in soft tissue inflammations, peripheral operation
pain or pain in inflammatory joint diseases, in particular
rheumatism, by administration of a therapeutically active dose of
one of the aforementioned substituted cyclohexane-1,4-diamine
compounds, or of an aforementioned medicament.
[0230] A process for the production of the substituted
cyclohexane-1,4-diamine compounds as outlined in the following
description and examples is also important.
[0231] Particularly suitable in this connection is a process,
hereinafter termed main process, for the production of a
substituted cyclohexane-1,4-diamine compound comprising the
following steps:
[0232] a) a cyclohexane-1,4-dione according to formula II and
protected by the groups S.sup.1 and S.sup.2 is reacted in the
presence of a compound of the formula HNR.sup.01 R.sup.02 with a
cyanide, preferably potassium cyanide, to form a protected
N-substituted 1-amino-4-oxocyclohexane carbonitrile compound
according to formula III; 3
[0233] is then optionally acylated, alkylated or sulfonated in an
arbitrary order and optionally repeatedly, and/or in the case of
compounds where R.sup.01 and/or R.sup.02 and/or R.sup.06 denotes H
protected with a protective group, a protective group is cleaved at
least once and optionally acylated, alkylated or sulfonated, and/or
in the case of compounds where R.sup.01 and/or R.sup.02 and/or
R.sup.06 are H, a protective group is introduced at least once and
optionally acylated, alkylated or sulfonated,
[0234] b) the aminonitrile according to formula III is reacted with
organometallic reagents, preferably Grignard or organolithium
reagents of the formula metal-R.sup.3, so that a compound according
to formula IVa is formed; 4
[0235] is then optionally acylated, alkylated or sulfonated in an
arbitrary order and optionally repeatedly, and/or in the case of
compounds where R.sup.01 and/or R.sup.02 and/or R.sup.06 denotes H
protected by a protective group, a protective group is split off at
least once and optionally acylated, alkylated or sulfonated, and/or
in the case of compounds where R.sup.01 and/or R.sup.02 and/or
R.sup.06 denote H, a protective group is introduced at least once
and optionally acylated, alkylated or sulfonated,
[0236] c) the protective groups S.sup.1 and S.sup.2 are cleaved
from the compound according to the formula IVa so that a
4-substituted 4-aminocyclohexanone compound according to formula IV
is formed; 5
[0237] which is then optionally acylated, alkylated or sulfonated
in an arbitrary order and optionally repeatedly, and/or in the case
of compounds where R.sup.01 and/or R.sup.02 and/or R.sup.06 denote
H protected by a protective group, a protective group is cleaved at
least once and optionally acylated, alkylated or sulfonated, and/or
in the case of compounds where R.sup.01 and/or R.sup.02 and/or
R.sup.06 denote H a protective group is introduced at least once
and optionally acylated, alkylated or sulfonated,
[0238] d) the 4-substituted 4-aminocyclohexanone compound according
to formula IVa is reductively aminated with a compound of the
formula HNR.sup.04R.sup.05 so that a cyclohexane-1,4-diamine
compound according to formula V is formed; 6
[0239] is then optionally acylated, alkylated or sulfonated in an
arbitrary order and optionally repeatedly, and/or in the case of
compounds where R.sup.01 and/or R.sup.02 and/or R.sup.04 and/or
R.sup.05 and/or R.sup.06 denote H protected by a protective group,
a protective group is cleaved at least once and the product is
optionally acylated, alkylated or sulfonated, and/or in the case of
compounds where R.sup.01 and/or R.sup.02 and/or R.sup.04 and/or
R.sup.05 and/or R.sup.06 denote H, a protective group is introduced
at least once and optionally acylated, alkylated or sulfonated to
form a compound according to formula I,
[0240] wherein R.sup.1, R.sup.2, R.sup.3, R.sup.4 and R.sup.5 have
the same meanings as the compounds used according to formula I
[0241] and
[0242] R.sup.01 and R.sup.02 independently of one another are
selected from H; H provided with a protective group;
C.sub.1-8-alkyl or C.sub.3-8-cycloalkyl, in each case saturated or
unsaturated, branched or unbranched, singly or multiply substituted
or unsubstituted; aryl or heteroaryl, in each case singly or
multiply substituted or unsubstituted; or aryl,
C.sub.3-8-cycloalkyl or heteroaryl bound via C.sub.1-3-alkylene, in
each case singly or multiply substituted or unsubstituted;
[0243] or the radicals R.sup.01 and R.sup.02 together form a ring
and denote CH.sub.2CH.sub.2OCH.sub.2CH.sub.2,
CH.sub.2CH.sub.2NR.sup.06CH.sub- .2CH.sub.2 or
(CH.sub.2).sub.3-6,
[0244] where R.sup.06 is selected from H; H provided with a
protective group; C.sub.1-8-alkyl or C.sub.3-8-cycloalkyl, in each
case saturated or unsaturated, branched or unbranched, singly or
multiply substituted or unsubstituted; aryl or heteroaryl, in each
case singly or multiply substituted or unsubstituted; or aryl,
C.sub.3-8-cycloalkyl or heteroaryl bound via C.sub.1-3-alkylene and
in each case singly or multiply substituted or unsubstituted;
[0245] R.sup.04 is selected from H, H provided with a protective
group; C.sub.1-8-alkyl, saturated or unsaturated, branched or
unbranched, singly or multiply substituted or unsubstituted;
[0246] R.sup.05 is selected from H, H provided with a protective
group; C.sub.3-8-cycloalkyl, aryl or heteroaryl, in each case
unsubstituted or singly or multiply substituted;
--CHR.sup.11R.sup.12, --CHR.sup.11--CH.sub.2R.sup.12,
--CHR.sup.11--CH.sub.2--R.sup.12,
--CHR.sup.11--CH.sub.2--CH.sub.2--CH.sub.2R.sup.12, --C(Y)R.sup.12,
--C(Y)--CH.sub.2R.sup.12, --C(Y)--CH.sub.2--CH.sub.2R.sup.12 or
--C(Y)--CH.sub.2--CH.sub.2--CH.sub.2R.sup.12
[0247] where Y=H.sub.2,
[0248] where R.sup.11 is selected from
[0249] H, C.sub.1-7-alkyl that is saturated or unsaturated,
branched or unbranched, singly or multiply substituted or
unsubstituted;
[0250] and where R.sup.12 is selected from
[0251] H; C.sub.3-8-cycloalkyl, aryl or heteroaryl, in each case
unsubstituted or singly or multiply substituted,
[0252] or R.sup.04 and R.sup.05 together form a heterocycle with
between 3 and 8 atoms in the ring, which is saturated or
unsaturated, singly or multiply substituted or unsubstituted,
[0253] and S.sup.1 and S.sup.2 independently of one another are
selected from protective groups or together denote a protective
group, preferably monoacetal.
[0254] In this connection alkylation also denotes a reductive
amination since it leads to the same result.
[0255] Also important is a process, hereinafter termed alternative
process, for the production of a substituted
cyclohexane-1,4-diamine compound comprising the following
steps:
[0256] a) a cyclohexane-1,4-dione according to formula II and
protected by the groups S.sup.1 and S.sup.2 is reductively aminated
with a compound of the formula HNR.sup.04R.sup.05 so that a
4-aminocyclohexanone compound according to formula VI is obtained;
7
[0257] is then optionally acylated, alkylated or sulfonated in an
arbitrary order and optionally repeatedly, and/or in the case of
compounds where R.sup.04 and/or R.sup.05 denote H protected by a
protective group, a protective group is cleaved at least once and
optionally acylated, alkylated or sulfonated, and/or in the case of
compounds where R.sup.04 and/or R.sup.05 denote H, a protective
group is introduced at least once and optionally acylated,
alkylated or sulfonated,
[0258] b) the 4-aminocyclohexanone compound according to formula VI
is reacted in the presence of a compound of the formula
HNR.sup.01R.sup.02 with a cyanide, preferably potassium cyanide, to
form a cyclohexanone nitrile compound of the formula VII, 8
[0259] is then optionally acylated, alkylated or sulfonated in an
arbitrary order and optionally repeatedly, and/or in the case of
compounds where R.sup.01 and/or R.sup.02 and/or R.sup.04 and/or
R.sup.05 and/or R.sup.06 denote H protected by a protective group,
a protective group is cleaved at least once and optionally
acylated, alkylated or sulfonated and/or in the case of compounds
where R.sup.01 and/or R.sup.02 and/or R.sup.04 and/or R.sup.05
and/or R.sup.06 denote H, a protective group is introduced at least
once and optionally acylated, alkylated or sulfonated,
[0260] c) the cyclohexanone nitrile compound of the formula VII is
reacted with organometallic reagents, preferably Grignard or
organolithium reagents of the formula metal-R.sup.3 and the
protective groups S.sup.1 and S.sup.2 are then cleaved so that a
cyclohexane-1,4-diamine compound according to formula V is formed,
9
[0261] is then optionally acylated, alkylated or sulfonated in an
arbitrary order and optionally repeatedly, and/or in the case of
compounds where R.sup.01 and/or R.sup.02 and/or R.sup.04 and/or
R.sup.05 and/or R.sup.06 denote H protected by a protective group,
a protective group is cleaved at least once and optionally
acylated, alkylated or sulfonated, and/or in the case of compounds
where R.sup.01 and/or R.sup.02 and/or R.sup.04 and/or R.sup.05
and/or R.sup.06 denote H, a protective group is introduced at least
once and optionally acylated, alkylated or sulfonated until a
compound according to formula I is formed,
[0262] wherein R.sup.1, R.sup.2, R.sup.3, R.sup.4 and R.sup.5 have
the meanings given for the compounds used according to formula
I,
[0263] and
[0264] R.sup.01 and R.sup.02 independently of one another are
selected from H; H provided with a protective group;
C.sub.1-8-alkyl or C.sub.1-8-cycloalkyl, in each case saturated or
unsaturated, branched or unbranched, singly or multiply substituted
or unsubstituted; aryl or heteroaryl, in each case singly or
multiply substituted or unsubstituted; or aryl,
C.sub.3-8-cycloalkyl or heteroaryl bound via C.sub.1-3-alkylene, in
each case singly or multiply substituted or unsubstituted;
[0265] or the radicals R.sup.01 and R.sup.02 together form a ring
and denote CH.sub.2CH.sub.2OCH.sub.2CH.sub.2,
CH.sub.2CH.sub.2NR.sup.06CH.sub- .2CH.sub.2 or
(CH.sub.2).sub.3-6,
[0266] where R.sup.06 is selected from H; H provided with a
protected group; C.sub.1-8-alkyl or C.sub.3-8-cycloalkyl, in each
case saturated or unsaturated, branched or unbranched, singly or
multiply substituted or unsubstituted; aryl or heteroaryl, in each
case singly or multiply substituted or unsubstituted; or aryl,
C.sub.3-8-cycloalkyl or heteroaryl bound via C.sub.1-3-alkylene, in
each case singly or multiply substituted or unsubstituted;
[0267] R.sup.04 is selected from H, H provided with a protective
group; C.sub.1-8-alkyl that is saturated or unsaturated, branched
or unbranched, singly or multiply substituted or unsubstituted;
[0268] R.sup.05 is selected from H provided with a protective
group; C.sub.3-8-cycloalkyl, aryl or heteroaryl, in each case
unsubstituted or singly or multiply substituted;
--CHR.sup.11R.sup.12, --CHR.sup.11--CH.sub.12R.sup.12,
--CHR.sup.11--CH.sub.2--CH.sub.2R.sup.12- ,
--CHR.sup.11--CH.sub.2--CH.sub.2--CH.sub.2R.sup.12, --C(Y)R.sup.12,
--C(Y)--CH.sub.2R.sup.12, --C(Y)--CH.sub.2--CH.sub.2R.sup.12 or
--C(Y)--CH.sub.2--CH.sub.2--CH.sub.2R.sup.12
[0269] where Y=H.sub.2,
[0270] where R.sup.11 is selected from
[0271] H, C.sub.1-7-alkyl that is saturated or unsaturated,
branched or unbranched, singly or multiply substituted or
unsubstituted;
[0272] and where R.sup.12 is selected from
[0273] H; C.sub.3-8-cycloalkyl, aryl or heteroaryl, in each case
unsubstituted or singly or multiply substituted,
[0274] or R.sup.04 and R.sup.05 together form a heterocycle with
between 3 and 8 atoms in the ring that is saturated or unsaturated;
singly or multiply substituted or unsubstituted,
[0275] and S.sup.1 and S.sup.2 independently of one another are
selected from protective groups or together denote a protective
group, preferably monoacetal.
[0276] For both processes it is preferred if the protective groups
at H in the case of R.sup.01, R.sup.02, R.sup.04, R.sup.05 and/or
R.sup.06 are selected from alkyl, benzyl or carbamates, for example
FMOC, Z or Boc.
[0277] Furthermore, it is preferred for the main process if the
reductive amination in step d. takes place in the presence of
ammonium formate, ammonium acetate or NaCNBH.sub.3.
[0278] For the main process a particularly advantageous
modification is also if, instead of the reductive amination with
HNR.sup.04R.sup.05 in step d), the compound IV is reacted with
hydroxylamine and is reduced after oxime formation.
[0279] It is also advantageous for the alternative process if in
step b) the radical R.sup.01 in the formula HNR.sup.01R.sup.02
denotes H, the reaction with the cyanide is carried out with TMSCN,
and a protective group is then optionally introduced at
R.sup.01.
[0280] The invention is illustrated further hereinafter by means of
examples, without however being restricted thereto.
EXAMPLES
[0281] The following examples serve to illustrate the invention in
more detail, without however restricting the general concept of the
invention.
[0282] The yields of the prepared compounds are not optimised.
[0283] All temperatures are uncorrected.
[0284] The term "ether" denotes diethyl ether, "EE" denotes ethyl
acetate and "DCM" denotes dichloromethane. The term "equivalent"
denotes quantitative equivalent, "m.p." denotes melting point or
melting point range, "RT" denotes room temperature, "vol. %"
denotes volume percent, "m %" denotes weight percent and "M"
denotes the concentration in mole/l.
[0285] Silica gel 60 (0.040-0.063 mm) from E. Merck, Darmstadt, was
used as stationary phase for the column chromatography.
[0286] The thin layer chromatography investigations were carried
out with HPTLC precoated plates, silica gel 60 F 254, from E.
Merck, Darmstadt.
[0287] The mixture ratios of solvents for chromatographic
investigations are always specified in volume/volume.
Example 1
[0288] N'-benzyl-N,N-dimethyl-1-phenylcyclohexane-1,4-diamine
hydrochloride, non-polar diastereomer
[0289] 200 ml of methanol, 1680 ml of aqueous dimethylamine
solution (40 m %), 303 g of dimethylamine hydrochloride and 200 g
of potassium cyanide were added to 200 g of
1,4-dioxaspiro[4.5]decan-8-one and stirred for ca. 65 hours. The
resultant white suspension was extracted four times with 800 ml of
ether each time, the combined extracts were concentrated by
evaporation, the residue was taken up in ca. 500 ml of
dichloromethane and the phases were separated. The dichloromethane
phase was dried over sodium sulfate, filtered and concentrated by
evaporation. 265 g of
8-dimethylamino-1,4-dioxaspiro[4.5]decane-8-carbonitrile were
obtained as a white solid.
[0290] 50.0 g of
8-dimethylamino-1,4-dioxaspiro[4.5]decane-8-carbonitrile were
dissolved in 400 ml of tetrahydrofuran of analysis purity, 216 ml
of a commercially obtainable 2 M solution of phenyl magnesium
chloride in tetrahydrofuran were added dropwise under a nitrogen
atmosphere while cooling in an ice bath, and the whole was stirred
overnight while heating to room temperature. The reaction mixture
was worked up by adding 200 ml of ice-cold ammonium chloride
solution (20 m %) while stirring and cooling in an ice bath, and
the phases were separated after 30 minutes. The aqueous phase was
extracted twice with 250 ml of ether each time, the extracts were
combined with the organic phase, washed with 200 ml of water
followed by 200 ml of saturated sodium chloride solution, dried
over sodium sulfate, filtered and concentrated by evaporation. 60.0
g of dimethyl-(8-phenyl-1,4-dioxaspiro[4.5]dec-8-yl)-amine were
obtained.
[0291] 165 ml of hydrochloric acid (32 m %) were diluted with 100
ml of water, 60.0 g of
dimethyl-(8-phenyl-1,4-dioxaspiro[4.5]dec-8-yl)-amine were added to
this ca. 6 M hydrochloric acid and the whole was stirred for 24
hours. The reaction mixture was washed three times with 50 ml of
diethyl ether each time, adjusted alkaline (pH>10) with 100 ml
of sodium hydroxide (32 m %) and extracted three times with 100 ml
of dichloromethane each time. The extracts were combined, dried
over sodium sulfate, filtered and concentrated by evaporation. 36.1
g of 4-dimethylamino-4-phenylcyclohexanone were obtained.
[0292] 2.00 g of 4-dimethylamino-4-phenylcyclohexanone were
dissolved in 30 ml of tetrahydrofuran of analysis purity and 986 mg
of benzylamine followed by 794 .mu.l of glacial acetic acid were
added while stirring and cooling in an ice bath. 2.72 g of sodium
triacetoxy boron hydride were then added in portions within 15
minutes and the reaction mixture was stirred for ca. 65 hours. The
reaction mixture was worked up by adding 15 ml of 2 M sodium
hydroxide dropwise (pH>10) and extracted three times with 25 ml
of diethyl ether each time. The combined organic phases were then
washed twice with 20 ml of water each time, dried over sodium
sulfate, filtered and concentrated by evaporation. The crude
product obtained was chromatographed on silica gel with diethyl
ether under the addition of 1 volume percent of aqueous ammonia
solution (25 m %). 844 mg of the non-polar diastereomer of
N'-benzyl-N,N-dimethyl-1-phen- ylcyclohexane-1,4-diamine were
obtained, which were converted, by dissolving in 6.8 ml of
2-butanone and adding 27.1 .mu.l of water followed by 381 .mu.l of
chlorotrimethylsilane and stirring overnight, into 843 mg of the
corresponding hydrochloride.
Example 2
[0293] N'-benzyl-N,N-dimethyl-1-phenylcyclohexane-1,4-diamine
hydrochloride, polar diastereomer
[0294] As described for Example 1, 1.01 g of the polar diastereomer
of N'-benzyl-N,N-dimethyl-1-phenylcyclohexane-1,4-diamine were also
obtained, which were converted by dissolving in 8.1 ml of
2-butanone and addition of 32.5 .mu.l of water followed by 457
.mu.l of chlorotrimethylsilane and stirring overnight, into 781 mg
of the corresponding hydrochloride.
Example 3
[0295] 1,N'-dibenzyl-N,N-dimethylcyclohexane-1,4-diamine
hydrochloride, non-polar diastereomer
[0296] 50.0 g of
8-dimethylamino-1,4-dioxaspiro[4.5]decane-8-carbonitrile (see
Example 1) were dissolved in 400 ml of tetrahydrofuran of analysis
purity, 214 ml of a commercially obtainable 2 M solution of benzyl
magnesium chloride in tetrahydrofuran were added dropwise under a
nitrogen atmosphere while cooling in an ice bath, and the whole was
stirred overnight while heating to room temperature. The reaction
mixture was worked up by adding 200 ml of ice-cold ammonium
chloride solution (20 m %) while stirring and cooling in an ice
bath, and the phases were separated after 30 minutes. The aqueous
phase was extracted twice with 250 ml of ether each time, and the
extracts were combined with the organic phase, washed with 200 ml
of water followed by 200 ml of saturated sodium chloride solution,
dried over sodium sulfate, filtered and concentrated by
evaporation. 78.4 g of crude product were obtained, which consisted
mainly of (8-benzyl-1,4-dioxa-spiro[4.5]dec-8-yl)-dimethy- lamine
and was converted further without additional purification. 200 ml
of hydrochloric acid (32 m %) were diluted with 120 ml of water,
78.49 of crude
(8-benzyl-1,4-dioxa-spiro[4.5]dec-8-yl)-dimethylamine were added to
this ca. 6 M hydrochloric acid, and the whole was stirred for 24
hours. The reaction mixture was washed three times with 100 ml of
diethyl ether each time, adjusted alkaline (pH>10) with 100 ml
of sodium hydroxide (32 m %) while cooling in an ice bath and
extracted three times with 100 ml of dichloromethane each time. The
extracts were combined, dried over sodium sulfate, filtered and
concentrated by evaporation. 50.4 g of
4-benzyl-4-dimethylaminocyclohexanone were obtained.
[0297] 2.00 g of 4-benzyl-4-dimethylaminocyclohexanone were
dissolved in 30 ml of tetrahydrofuran of analysis purity and 926 mg
of benzylamine followed by 746 .mu.l of glacial acetic acid were
added while stirring in an ice bath. 2.56 g of sodium triacetoxy
boron hydride were then added in portions within 15 minutes and the
reaction mixture was stirred for a further ca. 65 hours. The
reaction mixture was worked up by adding 15 ml of 2 M sodium
hydroxide dropwise (pH>10) and extracted three times with 25 ml
of diethyl ether each time. The combined organic phases were then
washed twice with 20 ml of water each time, dried over sodium
sulfate, filtered and concentrated by evaporation. The crude
product obtained was chromatographed on silica gel with diethyl
ether under the addition of 1 volume percent of aqueous ammonia
solution (25 m %). 774 mg of the non-polar diastereomer of
1,N'-dibenzyl-N,N-dimethylcyclohexane-1,- 4-diamine were obtained,
which were converted by dissolving in 6.2 ml of 2-butanone and
adding 23.8 .mu.l of water followed by 334 .mu.l of
chlorotrimethylsilane and stirring overnight, into 731 mg of the
corresponding hydrochloride.
Example 4
[0298] 1,N'-dibenzyl-N,N-dimethylcyclohexane-1,4-diamine
hydrochloride, polar diastereomer
[0299] As described for Example 3, 820 mg of the polar diastereomer
of 1,N'-dibenzyl-N,N-dimethylcyclohexane-1,4-diamine were also
obtained, which were converted by dissolving in 6.6 ml of
2-butanone and addition of 25.2 .mu.l of water followed by 354
.mu.l of chlorotrimethylsilane and stirring overnight, into 793 mg
of the corresponding hydrochloride.
Example 5
[0300] N-(4-benzyl-4-dimethylaminocyclohexyl)-N-propylbenzamide
hydrochloride
[0301] 6.00 g of 4-benzyl-4-dimethylaminocyclohexanone (see Example
3) were dissolved in 90 ml of tetrahydrofuran of analysis purity
and 1.53 g of n-propylamine followed by 3.36 ml of glacial acetic
acid were added while stirring in an ice bath. 7.68 g of sodium
triacetoxy boron hydride were then added in portions within 15
minutes and the reaction mixture was stirred for ca. 65 hours. The
reaction mixture was worked up by adding 45 ml of 2 M sodium
hydroxide dropwise (pH>10) and extracted three times with 50 ml
of diethyl ether each time. The combined organic phases were washed
twice with 50 ml of water each time, dried over sodium sulfate,
filtered and concentrated by evaporation. The crude product
obtained (6.43 g) was chromatographed on silica gel with diethyl
ether under the addition of 5 volume percent of aqueous ammonia
solution (25 m %). 707 mg of the non-polar diastereomer of
1-benzyl-N,N-dimethyl-N'-prop- ylcyclohexane-1,4-diamine were
obtained.
[0302] 700 mg of the non-polar diastereomer of
1-benzyl-N,N-dimethyl-N'-pr- opylcyclohexane-1,4-diamine were
dissolved in 10 ml of dichloromethane and 370 .mu.l of
triethylamine and ca. 10 mg of DMAP (4-dimethylaminopyridine- )
were added. 311 .mu.l of benzoyl chloride were added dropwise while
cooling in an ice/methanol bath and the reaction mixture was then
stirred overnight while heating to room temperature. The reaction
mixture was worked up by adding 10 ml of 5 M KOH solution and 10 ml
of water, stirred for 10 minutes, extracted three times with 20 ml
of dichloromethane each time, and the combined extracts were dried
over magnesium sulfate, filtered and concentrated by evaporation.
909 mg of N-(4-benzyl-4-dimethylaminocyclohexyl)-N-propylbenzamide
hydrochloride were prepared from the obtained product (834 mg)
using water and chlorotrimethylsilane as described for Example
1.
Example 6
[0303] N,N-dimethyl-1-phenyl-N'-propylcyclohexane-1,4-diamine
hydrochloride, non-polar diastereomer
[0304] 10.0 g of 4-dimethylamino-4-phenylcyclohexanone were
dissolved in 160 ml of tetrahydrofuran of analysis purity and 2.72
g of n-propylamine followed by 5.97 ml of glacial acetic acid were
added while stirring in an ice bath. 13.6 g of sodium triacetoxy
boron hydride were then added in portions within 15 minutes and the
reaction mixture was stirred for ca. 65 hours. The reaction mixture
was worked up by adding 85 ml of 2 M sodium hydroxide (pH>10)
dropwise and extracted three times with 100 ml of diethyl ether
each time. The combined organic phases were then washed twice with
100 ml of water each time, dried over sodium sulfate, filtered and
concentrated by evaporation. 5.00 g of the crude product obtained
(9.79 g) were chromatographed on silica gel with diethyl ether to
which 1 volume percent of aqueous ammonia solution (25 m %) was
added and with an addition of methanol increasing from 1 volume
percent to 40 volume percent. 2.79 g of the non-polar diastereomer
and 1.33 g of the polar diastereomer of
N,N-dimethyl-1-phenyl-N'-propylcyclohexane-1,4-diam- ine were
obtained. 253 mg of the corresponding hydrochloride were obtained
from a sample of 356 mg of the non-polar diastereomer, using water
and chlorotrimethylsilane in 2-butanone as described for Example
1.
Example 7
[0305] N-(4-dimethylamino-4-phenylcyclohexyl)-N-propylbenzamide
hydrochloride, non-polar diastereomer
[0306] 1.00 g of the non-polar diastereomer of
N,N-dimethyl-1-phenyl-N'-pr- opylcyclohexane-1,4-diamine (see
Example 6) were dissolved in 15 ml of dichloromethane and 560 .mu.l
of triethylamine and ca. 10 mg of DMAP were added. 468 .mu.l of
benzoyl chloride were added dropwise while cooling in an
ice/methanol bath and the reaction mixture was then stirred
overnight while heating to room temperature. The reaction mixture
was worked up by adding 12 ml of 5 M KOH solution and 12 ml of
water, stirred for 10 minutes, extracted three times with 25 ml of
dichloromethane each time, and the combined extracts were dried
over magnesium sulfate, filtered and concentrated by evaporation.
1.01 g of the non-polar diastereomer of
N-(4-benzyl-4-dimethylamino-cyclohexyl)-N-propylbenzamide
hydrochloride were prepared from the obtained product (1.31 g) as
described for Example 1, using water and chlorotrimethylsilane in
2-butanone.
Example 8
[0307] N-(4-dimethylamino-4-phenylcyclohexyl)-N-propylbenzamide
hydrochloride, polar diastereomer
[0308] 1.00 g of the polar diastereomer of
N,N-dimethyl-1-phenyl-N'-propyl- cyclohexane-1,4-diamine (see
Example 6) were dissolved in 15 ml of dichloromethane and 560 .mu.l
of triethylamine and ca. 10 mg of DMAP were added. 468 .mu.l of
benzoyl chloride were added dropwise while cooling in an
ice/methanol bath and the reaction mixture was then stirred
overnight while heating to room temperature. The reaction mixture
was worked up by adding 12 ml of 5 M KOH solution and 12 ml of
water, stirred for 10 minutes, extracted three times with 25 ml of
dichloromethane each time, and the combined extracts were dried
over magnesium sulfate, filtered and concentrated by evaporation.
752 mg of the polar diastereomer of
N-(4-benzyl-4-dimethylamino-cyclohexyl)-N-propylbenzamide
hydrochloride were prepared as described for Example 1 using water
and chlorotrimethyl-silane in 2-butanone.
Example 9
[0309] 1,N'-dibenzyl-N,N,N'-trimethylcyclohexane-1,4-diamine
hydrochloride, non-polar diastereomer
[0310] 10.0 g of 4-benzyl-4-dimethylaminocyclohexanone (see Example
3) were dissolved in 150 ml of tetrahydrofuran of analysis purity
and 5.24 g of benzylmethylamine followed by 5.60 ml of glacial
acetic acid were added while stirring in an ice bath. 12.8 g of
sodium triacetoxy boron hydride were then added in portions within
15 minutes and the reaction mixture was stirred overnight. The
reaction mixture was worked up by adding 75 ml of 2 M sodium
hydroxide (pH>10) dropwise and extracted three times with 100 ml
of diethyl ether each time. The combined organic phases were then
washed twice with 100 ml of water each time, dried over sodium
sulfate, filtered and concentrated by evaporation. The crude
product obtained (13.1 g) was chromatographed on silica gel with
ethyl acetate and an addition of methanol increasing from 0 volume
percent to 100 volume percent.
[0311] In addition to a mixed fraction of 5.23 g, 5.37 g of the
non-polar and 1.20 g of the polar diastereomer of
N,N-dimethyl-1-phenyl-N'-propylcy- clohexane-1,4-diamine were
obtained. 5.44 g of the corresponding hydrochloride were obtained
from the non-polar diastereomer as described for Example 1 using
water and chlorotrimethylsilane in 2-butanone.
Example 10
[0312] 1,N'-dibenzyl-N,N,N'-trimethylcyclohexane-1,4-diamine
hydrochloride, polar diastereomer
[0313] 1.24 g of the corresponding hydrochloride were obtained as
described for Example 9 from 1.20 g of the polar diastereomer of
1,N'-dibenzyl-N,N,N'-trimethylcyclohexane-1,4-diamine.
Example 11
[0314] N-(4-benzyl-4-dimethylaminocyclohexyl)-N-methylbenzamide
hydrochloride, polar diastereomer
[0315] 15.0 g of 4-benzyl-4-dimethylaminocyclohexanone (see Example
3) were dissolved in 225 ml of tetrahydrofuran of analysis purity
and 4.38 g of methylamine hydrochloride, 8.9 ml of triethylamine
and 8.40 ml of glacial acetic acid were added while stirring in an
ice bath. 19.2 g of sodium triacetoxy boron hydride were then added
in portions within 15 minutes and the reaction mixture was stirred
overnight. The reaction mixture was worked up by adding 110 ml of 2
M sodium hydroxide (pH>10) dropwise and extracted three times
with 200 ml of diethyl ether each time. The combined organic phases
were washed twice with 200 ml of water each time, dried over sodium
sulfate, filtered and concentrated by evaporation. The crude
product obtained (15.0 g) was chromatographed on silica gel with
methanol with the addition of 1 volume percent of aqueous ammonia
solution (25 m %). 11.6 g of the still substantially impure product
were obtained, which was chromatographed again on silica gel with
ethyl acetate and an addition of methanol increasing from 25 volume
percent to 50 volume percent. 6.67 g of
1-benzyl-N,N,N'-trimethylcyclohex- ane-1,4-diamine were obtained as
a cis/trans mixture.
[0316] 3.00 g of 1-benzyl-N,N,N'-trimethylcyclohexane-1,4-diamine
were dissolved in 50 ml of dichloromethane and 1.78 ml of
triethylamine and ca. 10 mg of DMAP were added. 1.41 ml of benzoyl
chloride were added dropwise while cooling in an ice/methanol bath
and the reaction mixture was then stirred overnight while heating
to room temperature. The reaction mixture was worked up by adding
50 ml of 5 M KOH solution and 50 ml of water, stirred for 10
minutes, extracted three times with 50 ml of dichloromethane each
time, and the combined extracts were dried over magnesium sulfate,
filtered and concentrated by evaporation. The crude product
obtained (3.61 g) was chromatographed on silica gel with
methanol/ether (1:1). 231 g of the polar diastereomer of
N-(4-benzyl-4-dimethylaminocyclohexyl)-N-methylbenzamide were
obtained, from which 188 mg of the corresponding hydrochloride were
prepared as described for Example 1 using water and
chlorotrimethylsilane in 2-butanone.
Example 12
[0317] N-(4-benzyl-4-dimethylaminocyclohexyl)-N-ethylbenzamide
hydrochloride, polar diastereomer
[0318] 15.0 g of 4-benzyl-4-dimethylaminocyclohexanone (see Example
3) were dissolved in 225 ml of tetrahydrofuran of analysis purity
and 2.89 g of ethylamine followed by 8.40 ml of glacial acetic acid
were added while stirring in an ice bath. 19.2 g of sodium
triacetoxy boron hydride were then added in portions within 15
minutes and the reaction mixture was stirred overnight. The
reaction mixture was worked up by adding 110 ml of 2 M sodium
hydroxide dropwise (pH>10) and extracted three times with 200 ml
of diethyl ether each time. The combined organic phases were washed
twice with 200 ml of water each time, dried over sodium sulfate,
filtered and concentrated by evaporation. The crude product
obtained (15.7 g) was chromatographed on silica gel with methanol
with the addition of 1 volume percent of aqueous ammonia solution
(25 m %). 14.1 g of the still substantially impure product were
obtained, which was chromatographed again on silica gel with
methanol with the addition of 1 volume percent of aqueous ammonia
solution (25 m %). 12.1 g of
1-benzyl-N'-ethyl-N,N-dimethylcyclohexane-1,4-diamine were obtained
as a cis/trans mixture.
[0319] 3.00 g of
1-benzyl-N'-ethyl-N,N-dimethylcyclohexane-1,4-diamine were
dissolved in 50 ml of dichloromethane and 1.68 ml of triethylamine
and ca. 10 mg of DMAP were added. 1.40 ml of benzoyl chloride were
added dropwise while cooling in an ice/methanol bath and the
reaction mixture was then stirred overnight while heating to room
temperature. The reaction mixture was worked up by adding 50 ml of
5 M KOH solution and 50 ml of water, stirred for 10 minutes,
extracted three times with 50 ml of dichloromethane each time, and
the combined extracts were dried over magnesium sulfate, filtered,
and concentrated by evaporation. The crude product obtained (4.05
g) was chromatographed on silica gel with methanol/ether (1:1).
1.09 g of the polar diastereomer of
N-(4-benzyl-4-dimethylaminocyclohexyl)-N-ethylbenzamide were
obtained, from which 1.01 mg of the corresponding hydrochloride
were prepared as described for Example 1 using water and
chlorotrimethylsilane in 2-butanone.
Example 13
[0320]
1-benzyl-N'-(1H-indol-3-ylmethyl)-N,N-dimethylcyclohexane-1,4-diami-
ne dihydrochloride
[0321] 14.5 g of 3-formylindole and 13.9 g of hydroxylamine
hydrochloride were boiled for two hours in a mixture of dry
pyridine (80 ml) and absolute ethanol (80 ml). The initially yellow
reaction mixture turned deep red during this time. The solvent
mixture was then distilled off in vacuo. In order to remove the
pyridine the residue was evaporated to dryness three times with
ethanol (each time 30 ml). Water (100 ml) was then added to the
residue and the mixture was vigorously stirred for 30 minutes using
a magnetic stirrer. The reaction solution with the pink-coloured
solid that had formed was cooled for 2 hours in a cooling cabinet.
The oxime obtained was suction filtered, washed with water
(3.times.25 ml) and dried in a desiccator. 15.6 g of
1H-indole-3-carbaldehyde-(Z)-oxime with a melting point of
190.degree.-193.degree. C. were obtained.
[0322] 4.8 g of 1H-indole-3-carbaldehyde-(Z)-oxime were suspended
(sparingly soluble) in methanol (100 ml) and diluted with 5 M
sodium hydroxide (100 ml). The reaction vessel was continuously
flushed with a gentle stream of argon. Devarda's alloy (20 g) was
added in portions to the mixture. The rate of addition was governed
by the intensity of the reaction. The reaction was cooled from time
to time with iced water. The addition was completed after 2 hours,
following which the mixture was stirred for 30 minutes at RT and
then diluted with water (100 ml). The methanol was removed in vacuo
and the aqueous solution was extracted with ether (4.times.50 ml).
After drying and distilling off the ether the residue was purified
by recrystallisation from toluene (20 ml). 2.2 g of
C-(1H-indol-3-yl)-methylamine were obtained as a beige-coloured
solid with a melting point of 90.degree.-94.degree. C., which
quickly changed colour on exposure to light and RT. The product
could be stored for a few days in dark bottles and in a cooling
cabinet.
[0323] 292 mg of C-(1H-indol-3-yl)-methylamine were partially
dissolved in dry 1,2-dichloroethane (10 ml) under argon. After
addition of 463 mg of 4-benzyl-4-dimethylaminocyclohexanone (see
Example 3), glacial acetic acid (4 mmole) and sodium triacetoxy
boron hydride (550 mg) the suspension was stirred for 72 hours at
room temperature. The reaction mixture was worked up by adding
water (10 ml). The organic phase was separated and the aqueous
phase was extracted twice with ether and then made strongly
alkaline with sodium hydroxide. The product was re-extracted with
ethyl acetate (4.times.10 ml). A pale precipitate formed from the
combined ethyl acetate phases already during the working-up. The
precipitate was cooled and then suction filtered, washed twice with
cold ethyl acetate and dried. The product thereby obtained (235 mg)
was white and solid (m.p. 194.degree.-198.degree. C.). 217 mg were
dissolved hot in 2-butanone/ethanol (30 ml+10 ml) and saturated
ethanolic hydrochloric acid (1.5 ml; 1.85 M) was added at RT while
stirring. After 2 hours a precipitate had still not formed. Also,
no hydrochloride had precipitated after reducing the amount of
solvent and cooling. Accordingly the mixture was evaporated to
dryness at 40.degree. C. in vacuo and excess HCl was expelled. As
residue 260 mg of
1-benzyl-N'-(1H-indol-3-ylmethyl)-N,N-dimethylcyclohexane-1,4-diamine
dihydrochloride were obtained as a pale pink solid with an m.p. of
170.degree.-174.degree. C.
Example 14
[0324]
1-benzyl-N'-[2-(1H-indol-3-yl)-1-methylethyl]-N,N-dimethylcyclohexa-
ne-1,4-diamine, cis/trans mixture
[0325] 348 mg of DL-.alpha.-methyltryptamine were dissolved in dry
1,2-dichloroethane (10 ml) under argon (clear solution), 463 mg of
4-benzyl-4-dimethylaminocyclohexanone (see Example 3), and glacial
acetic acid (229 .mu.l) were added and the mixture was stirred for
1 hour at RT. 550 mg of sodium triacetoxy boron hydride were then
added and the suspension was stirred for a further 72 hours at RT.
The reaction mixture was worked up by adding water (20 ml), the
organic phase was separated and the aqueous phase was extracted
once with ether and then made strongly alkaline with sodium
hydroxide (pH>10). A gel-like precipitate was formed, which
dissolved in ethyl acetate. The aqueous phase was extracted with
ethyl acetate (4.times.10 ml). All the ethyl acetate phases were
combined, dried with sodium sulfate and evaporated to dryness. 766
mg of a mixture of cis- and trans-1-benzyl-N'-[2-(1H-indol-3-
-yl)-1-methylethyl]-N,N-dimethylcyclohexane-1,4-diamine were
obtained as a glass-like solid (m.p. 48.degree.-53.degree. C.).
Example 15
[0326] 1-benzyl-N'-indan-5-yl-N,N-dimethylcyclohexane-1,4-diamine
hydrochloride
[0327] 266 mg of 5-aminoindane and 462 mg of
4-benzyl-4-dimethylaminocyclo- hexanone (see Example 3) were
dissolved in dry 1,2-dichloroethane under argon and stirred with 2
g of sodium sulfate for 24 hours at RT. 600 mg of sodium triacetoxy
boron hydride were added to this mixture and stirred for 2 hours at
RT. For working-up the reaction mixture was concentrated by
evaporation and the residue was adjusted to pH 11 with 5 M sodium
hydroxide. The alkaline phase was diluted with water (10 ml) and
extracted with ethyl acetate (4.times.20 ml). The combined extracts
were dried over sodium sulfate, filtered and concentrated by
evaporation. The crude product was chromatographed on silica gel
with ethyl acetate. 440 mg of
1-benzyl-N'-indan-5-yl-N,N-dimethylcyclohexane-1,4-diamine were
obtained as a colourless oil. In order to prepare the hydrochloride
the base was dissolved in 2-butanone (8 ml) and 1.85 M ethanolic
hydrochloric acid (1.75 ml) was added. The precipitated solid was
suction filtered and dried. 280 mg of
1-benzyl-N'-indan-5-yl-N,N-dimethylcyclohexane-1,4-diami- ne
hydrochloride were obtained as a white solid (m.p.
200.degree.-203.degree. C.).
Example 16
[0328] 1-benzyl-N'-indan-1-yl-N,N-dimethylcyclohexane-1,4-diamine
dihydrochloride, cis/trans mixture
[0329] 266 mg of 1-aminoindane and 462 mg of
4-benzyl-4-dimethylaminocyclo- hexanone (see Example 3) were
dissolved in dry 1,2-dichloroethane under argon and stirred with 2
g of sodium sulfate for 24 hours at RT. 600 mg of sodium triacetoxy
boron hydride were added to this mixture and stirred for 2 hours at
RT. For working-up the reaction mixture was concentrated by
evaporation and the residue was adjusted to pH 11 with 5 M sodium
hydroxide. The alkaline phase was diluted with water (10 ml) and
extracted with ethyl acetate (4.times.20 ml). The combined extracts
were dried over sodium sulfate, filtered and concentrated by
evaporation. The crude product was chromatographed on silica gel
with ethyl acetate. 696 mg of
1-benzyl-N'-indan-1-yl-N,N-dimethylcyclohexane-1,4-diamine were
obtained as a colourless oil. In order to prepare the hydrochloride
the base was dissolved in 2-butanone (10 ml) and 1.85 M ethanolic
hydrochloric acid (2.80 ml) was added. The precipitated solid was
suction filtered and dried. 540 mg of a mixture of cis- and
trans-1-benzyl-N'-indan-1-yl-N,N-dimethylcyclohexane-1,4-diamine
dihydrochloride was obtained as a white solid (m.p.
170.degree.-172.degree. C.).
Example 17
[0330]
N'-indan-1-yl-N,N-dimethyl-1-phenylcyclohexane-1,4-diamine
[0331] 266 mg of 1-aminoindane and 434 mg of
4-dimethylamino-4-phenylcyclo- hexanone were dissolved in dry
1,2-dichloroethane (10 ml) and THF (10 ml) under argon. Glacial
acetic acid (2 mmole) and sodium triacetoxy boron hydride (600 mg)
were added to this mixture and stirred for 24 hours at RT. For
working-up the reaction mixture was concentrated by evaporation and
the residue was adjusted to pH 11 with 5 M sodium hydroxide. The
alkaline phase was diluted with water (10 ml) and extracted with
ethyl acetate (5.times.20 ml). The combined extracts were dried
over sodium sulfate, filtered and concentrated by evaporation. The
crude product was chromatographed on silica gel with ethyl
acetate/ethanol (1:1). 200 mg of
N'-indan-1-yl-N,N-dimethyl-1-phenylcyclohexane-1,4-diamine were
obtained as a white solid (m.p. 99.degree.-101.degree. C.).
Example 18
[0332]
N'-(1H-indol-5-yl)-N,N-dimethyl-1-phenylcyclohexane-1,4-diamine
[0333] 264 mg of 5-aminoindane and 434 mg of
4-dimethylamino-4-phenylcyclo- hexanone were dissolved in dry
1,2-dichloroethane (10 ml) under argon. Glacial acetic acid (2
mmole) and sodium triacetoxy boron hydride (600 mg) were added to
this mixture and stirred for 24 hours at RT. For working-up the
reaction mixture was concentrated by evaporation and the residue
was adjusted to pH 11 with 5 M sodium hydroxide. The alkaline phase
was diluted with water (10 ml) and extracted with ethyl acetate
(4.times.20 ml). The combined extracts were dried over sodium
sulfate, filtered and concentrated by evaporation. The crude
product was chromatographed on silica gel with ethyl
acetate/ethanol (1:1). 315 mg of
N'-(1H-indol-5-yl)-N,N-dimethyl-1-phenylcyclohexane-1,4-diamine
were obtained as a white solid (m.p. 191.degree.-192.degree.
C.).
Example 19
[0334]
N'-(1H-indol-3-ylmethyl)-N,N-dimethyl-1-phenylcyclohexane-1,4-diami-
ne, cis/trans mixture
[0335] 292 mg of C-(1H-indol-3-yl)methylamine were dissolved in dry
1,2-dichloroethane (15 ml) and THF (5 ml) under argon to form an
almost clear solution. After addition of
4-dimethylamino-4-phenylcyclohexanone (435 mg), glacial acetic acid
(4 mmole) and sodium triacetoxy boron hydride (550 mg) a suspension
formed which was stirred for 72 hours at RT. For working-up water
(20 ml) was added to the reaction mixture and stirred vigorously
for 1 hour. The organic phase was separated and the aqueous phase
was extracted twice with ether (10 ml) and then made strongly
alkaline with 5 M sodium hydroxide. The aqueous phase was extracted
with ethyl acetate (4.times.10 ml). A solid thereby precipitated
out, which dissolved in ethyl acetate (50 ml) on heating. The
combined extracts were dried over sodium sulfate, filtered and
concentrated by evaporation. The crude product obtained (382 mg)
was recrystallised from a mixture of methanol (1 ml) and ethyl
acetate (5 ml). The precipitate was suction filtered and washed
with a small amount of cold ethyl acetate. 156 mg of
N'-(1H-indol-3-ylmethyl)-N,N-dimethyl-1--
phenylcyclohexane-1,4-diamine were obtained as a cis/trans
mixture.
Example 20
[0336]
N'-(1H-indol-3-ylmethyl)-N,N-dimethyl-1-phenylcyclohexane-1,4-diami-
ne, non-polar diastereomer
[0337] The mother liquor obtained in Example 19 was concentrated by
evaporation. 173 mg of the non-polar diastereomer of
N'-(1H-indol-3-ylmethyl)-N,N-dimethyl-1-phenylcyclohexane-1,4-diamine
were obtained (m.p. 170.degree.-178.degree. C.).
Example 21
[0338]
N'-[2-(1H-indol-3-yl)-ethyl]-N,N-dimethyl-1-phenylcyclohexane-1,4-d-
iamine, non-polar diastereomer
[0339] Tryptamine (320 mg) was dissolved in dry 1,2-dichloroethane
(10 ml) under argon. After addition of
4-dimethylamino-4-phenylcyclohexanone (435 mg), glacial acetic acid
(229 .mu.l) and sodium triacetoxy boron hydride (550 mg) the
suspension was stirred for 3 days at RT. For working-up water (20
ml) was added to the reaction mixture. The organic phase was
separated and the aqueous phase was extracted once with ether and
then made strongly alkaline with sodium hydroxide. The aqueous
phase was opalescently turbid at pH 10. The aqueous phase was
extracted with ethyl acetate (4.times.10 ml) and the extracts were
combined, dried over sodium sulfate, filtered and concentrated by
evaporation. The crude product obtained (674 mg) was recrystallised
twice from ethyl acetate (5 ml). 22 mg of the non-polar
diastereomer of N'-[2-(1H-indol-3-yl)-ethyl]-N,N-dime-
thyl-1-phenylcyclohexane-1,4-diamine were obtained (m.p.
134.degree.-138.degree. C.).
Example 22
[0340]
N'-[2-(1H-indol-3-yl)-ethyl]-N,N-dimethyl-1-phenylcyclohexane-1,4-d-
iamine, cis/trans mixture
[0341] As described for Example 21, 320 mg of
N'-[2-(1H-indol-3-yl)-ethyl]-
-N,N-dimethyl-1-phenylcyclohexane-1,4-diamine were also obtained as
a mixture of the cis/trans isomers (m.p. 149.degree.-153.degree.
C.).
Example 23
[0342] N'-indan-5-yl-N,N-dimethyl-1-phenylcyclohexane-1,4-diamine,
non-polar diastereomer
[0343] 5-aminoindane (266 mg) and
4-dimethylamin-4-phenylocyclohexanone (434 mg) were dissolved in
dry 1,2-dichloroethane (10 ml) under argon. Glacial acetic acid (2
mmole) and sodium triacetoxy boron hydride (600 mg) were added and
stirred for 24 hours at RT. For working-up the reaction mixture was
concentrated by evaporation and the residue was adjusted to pH 11
with 5 M sodium hydroxide. The alkaline phase was diluted with
water (10 ml) and extracted with ethyl acetate (4.times.20 ml). The
combined extracts were dried over sodium sulfate, filtered and
concentrated by evaporation. The crude product obtained was
chromatographed on silica gel with ethyl acetate/ethanol (1:1). 270
mg of the non-polar diastereomer of
N'-indan-5-yl-N,N-dimethyl-1-phenylcyclohex- ane-1,4-diamine were
obtained as a white solid (m.p. 162.degree.-164.degree. C.).
Example 24
[0344]
N'-[2-(1H-indol-3-yl)-1-methylethyl]-N,N-dimethyl-1-phenylcyclohexa-
ne-1,4-diamine, non-polar diastereomer
[0345] DL-.alpha.-methyltryptamine (348 mg, 2 mmole) was dissolved
in dry 1,2-dichloroethane (10 ml) under argon. After addition of
4-dimethylamino-4-phenylcyclohexanone (435 mg) and glacial acetic
acid (229 .mu.l) the mixture was stirred for 1 hour at RT. Sodium
triacetoxy boron hydride (550 mg) was then added and the suspension
was stirred for 4 days at RT. For working-up water (15 ml) was
added to the reaction mixture. The clear phases were separated and
the aqueous phase was washed with ether (10 ml) and then made
strongly alkaline with sodium hydroxide. The aqueous phase was
extracted with ethyl acetate (4.times.10 ml) and the combined
extracts were dried over sodium sulfate, filtered and concentrated
by evaporation. The crude product obtained (723 mg) was
recrystallised twice from a mixture of ethyl acetate/cyclohexane (2
ml/6 ml). A fraction of the non-polar diastereomer of
N'-[2-(1H-indol-3-yl)-1--
methylethyl]-N,N-dimethyl-1-phenylcyclohexane-1,4-diamine was
obtained (128 mg, m.p. 155.degree.-162.degree. C.).
Example 25
[0346]
N'-[2-(1H-indol-3-yl)-1-methylethyl]-N,N-dimethyl-1-phenylcyclohexa-
ne-1,4-diamine, cis/trans mixture
[0347] As described for Example 24, 375 mg of
N'-[2-(1H-indol-3-yl)-1-meth-
ylethyl]-N,N-dimethyl-1-phenylcyclohexane-1,4-diamine were also
obtained as a mixture of the cis/trans isomers (dark yellow
oil).
Example 26
[0348]
N'-[2-(5-benzyloxy-1H-indol-3-yl)-ethyl]-N,N-dimethyl-1-phenylcyclo-
hexane-1,4-diamine, cis/trans mixture
[0349] 5-benzyloxytryptamine (440 mg, 1.65 mmole) was dissolved in
dry 1,2-dichloroethane (14 ml) under argon (slightly turbid
solution). After addition of 4-dimethylamino-4-phenylcyclohexanone
(359 mg, 1.65 mmole) and glacial acetic acid (189 .mu.l, 3.3 mmole)
the mixture was stirred for 2 hours at RT. Sodium triacetoxy boron
hydride (462 mg) was then added and the suspension was stirred for
4 days at RT. For working-up water (15 ml) was added to the
reaction mixture. The phases were separated and the aqueous phase
was washed with ether (20 ml) and then made strongly alkaline with
sodium hydroxide. The aqueous phase was extracted with ether
(2.times.10 ml) and ethyl acetate (4.times.10 ml), and the combined
extracts were dried over sodium sulfate, filtered and concentrated
by evaporation. The crude product obtained (686 mg) was
recrystallised from a mixture of ethyl acetate/cyclohexane (35 ml/5
ml). 396 mg of
N'-[2-(5-benzyloxy-1H-indol-3-yl)-ethyl]-N,N-dimethyl-1-phenylc-
yclohexane-1,4-diamine were obtained as a cis/trans mixture (m.p.
130.degree.-134.degree. C.).
Example 27
[0350]
N'-(9H-fluoren-1-yl)-N,N-dimethyl-1-phenylcyclohexane-1,4-diamine
dihydrochloride
[0351] 1-aminofluorene (181 mg, 1 mmole) and
4-dimethylamino-4-phenylcyclo- hexanone (217 mg, 1 mmole) were
dissolved in dry 1,2-dichloroethane (10 ml) under argon. Glacial
acetic acid (1 mmole) and sodium triacetoxy boron hydride (300 mg)
were added to this mixture and stirred for 24 hours at RT. For
working-up the reaction mixture was concentrated by evaporation and
the residue was adjusted to pH 11 with 5 M sodium hydroxide. The
alkaline phase was diluted with water (10 ml) and extracted with
ethyl acetate (4.times.20 ml). The combined extracts were dried
over sodium sulfate, filtered and concentrated by evaporation. The
crude product was chromatographed on silica gel with ethyl
acetate/ethanol (1:1). 200 mg of
N'-(9H-fluoren-1-yl)-N,N-dimethyl-1-phen- ylcyclohexane-1,4-diamine
were obtained as a colourless oil, dissolved in 2-butanone (5 ml)
followed by the addition of 1.85 M ethanolic HCl (0.7 ml) for the
preparation of the hydrochloride. The N'-(9H-fluoren-1-yl)-N,-
N-dimethyl-1-phenylcyclohexane-1,4-diamine dihydrochloride obtained
was suction filtered and dried. (220 mg, m.p.
223.degree.-225.degree. C.).
Example 28
[0352] N'-indan-2-yl-N,N-dimethyl-1-phenylcyclohexane-1,4-diamine
dihydrochloride, cis/trans mixture
[0353] 2-aminoindane (266 mg, 2 mmole) and
4-dimethylamin-4-phenylocyclohe- xanone (434 mg, 2 mmole) were
dissolved in dry 1,2-dichloroethane (10 ml) under argon. Glacial
acetic acid (2 mmole) and sodium triacetoxy boron hydride (600 mg)
were added to this mixture and stirred for 24 hours at RT. For
working-up the mixture was concentrated by evaporation and the
residue was adjusted to pH 11 with 5 M sodium hydroxide. The
alkaline phase was diluted with water (10 ml) and extracted with
ethyl acetate (4.times.20 ml). The combined extracts were dried
over sodium sulfate, filtered and concentrated by evaporation. The
crude product was chromatographed on silica gel with ethyl
acetate/ethanol (1:1). 490 mg of
N'-indan-2-yl-N,N-dimethyl-1-phenylcyclo-hexane-1,4-diamine were
obtained as a white solid, which for the preparation of the
hydrochloride was dissolved in 2-butanone (10 ml) followed by the
addition of 1.85 M ethanolic HCl (2 ml). The mixture of cis- and
trans-N'-indan-2-yl-N,N-dim- ethyl-1-phenylcyclohexane-1,4-diamine
dihydrochloride that was obtained was suction filtered and dried
(540 mg, m.p. 224.degree.-226.degree. C.).
Example 29
[0354]
N'-(9H-fluoren-9-yl)-N,N-dimethyl-1-phenylcyclohexane-1,4-diamine
dihydrochloride, cis/trans mixture
[0355] 9-aminofluorene (362 mg, 2 mmole) and
4-dimethylamino-4-phenylcyclo- hexanone (434 mg, 2 mmole) were
dissolved in dry 1,2-dichloroethane (10 ml) under argon. Glacial
acetic acid (2 mmole) and sodium triacetoxy boron hydride (600 mg)
were added to this mixture and stirred for 24 hours at RT. For
working-up the reaction mixture was concentrated by evaporation and
the residue was adjusted to pH 11 with 5 M sodium hydroxide. The
alkaline phase was diluted with water (10 ml) and extracted with
ethyl acetate (5.times.20 ml). The combined extracts were dried
over sodium sulfate, filtered and concentrated by evaporation. The
crude product was chromatographed on silica gel with ethyl
acetate/ethanol (1:1). 440 mg of
N'-(9H-fluoren-9-yl)-N,N-dimethyl-1-phen- ylcyclohexane-1,4-diamine
were obtained as a white solid, which for the preparation of the
hydrochloride was dissolved in 2-butanone (10 ml) followed by the
addition of 1.85 M ethanolic HCl (1.55 ml). The mixture of
N'-(9H-fluoren-9-yl)-N,N-dimethyl-1-phenylcyclohexane-1,4-diamine
dihydrochloride that was obtained was suction filtered and dried
(460 mg, m.p. 202.degree.-205.degree. C.).
Example 30
[0356]
1-benzyl-N'-(9H-fluoren-9-yl)-N,N-dimethylcyclohexane-1,4-diamine
[0357] 1-aminofluorene (181 mg, 1 mmole) and
4-benzyl-4-dimethylaminocyclo- hexanone (231 mg, 1 mmole) were
dissolved in dry 1,2-dichloroethane (10 ml) under argon. Glacial
acetic acid (1 mmole) and sodium triacetoxy boron hydride (300 mg)
were added to this mixture and stirred for 24 hours at RT. For
working-up the reaction mixture was concentrated by evaporation and
the residue was adjusted to pH 11 with 5 M sodium hydroxide. The
alkaline phase was diluted with water (10 ml) and extracted with
ethyl acetate (4.times.20 ml). The combined extracts were dried
over sodium sulfate, filtered and concentrated by evaporation. The
crude product was chromatographed on silica gel with ethyl
acetate/ethanol (1:1). 150 mg of
1-benzyl-N'-(9H-fluoren-9-yl)-N,N-dimeth- ylcyclohexane-1,4-diamine
were obtained as a white solid (m.p. 123.degree.-125.degree.
C.)
Example 31
[0358]
1-benzyl-N'-(1H-indol-3-ylmethyl)-N,N-dimethylcyclohexane-1,4-diami-
ne, cis/trans mixture
[0359] 292 mg of C-(1H-indol-3-yl)-methylamine were partially
dissolved in dry 1,2-dichloroethane (10 ml) under argon. After
addition of 463 mg of 4-benzyl-4-dimethylaminocyclohexanone (see
Example 3), glacial acetic acid (4 mmole) and sodium triacetoxy
boron hydride (550 mg) the suspension was stirred for 72 hours at
room temperature. For working-up water (10 ml) was added to the
reaction mixture.
[0360] The organic phase was separated and the aqueous phase was
extracted twice with ether and then made strongly alkaline with
sodium hydroxide. The aqueous phase was re-extracted with ethyl
acetate (4.times.10 ml). A white precipitate formed from the
combined ethyl acetate phases during the processing. After cooling
this was suction filtered, washed twice with cold ethyl acetate and
dried. 235 mg of 1-benzyl-N'-(1H-indol-3-ylme-
thyl)-N,N-dimethylcyclohexane-1,4-diamine were obtained as a
cis/trans mixture (m.p. 194.degree.-198.degree. C.).
Example 32
[0361]
N,N-dimethyl-N'-(1-methyl-1H-indol-3-ylmethyl)-1-phenylcyclohexane--
1,4-diamine, cis/trans mixture
[0362] 450 mg of C-(1H-indol-3-yl)-methylamine were partially
dissolved in dry 1,2-dichloroethane (10 ml) under argon. After
addition of 609 mg of 4-dimethylamino-4-cyclohexanone, glacial
acetic acid (5.6 mmole), sodium sulfate (2 g) and sodium triacetoxy
boron hydride (770 mg) the suspension was stirred for 5 days at
room temperature. For working-up water (20 ml) was added to the
reaction mixture. The organic phase was separated and the aqueous
phase was washed twice with ether (5 ml) and then made strongly
alkaline with sodium hydroxide. The aqueous phase was extracted
with ether (2.times.5 ml) and ethyl acetate (4.times.10 ml), and
the combined extracts were dried over sodium sulfate, filtered and
concentrated by evaporation. The crude product obtained was
chromatographed on silica gel with methanol/triethylamine (100:1).
52 mg of
N,N-dimethyl-N'-(1-methyl-1H-indol-3-ylmethyl)-1-phenylcyclohexane-1,4-
-diamine were obtained as a cis/trans mixture.
Example 33
[0363]
N,N-dimethyl-N'-(1-methyl-1H-indol-3-ylmethyl)-1-phenylcyclohexane--
1,4-diamine, polar diastereomer
[0364] As described for Example 32, 106 mg of the polar
diastereomer of
N,N-dimethyl-N'-(1-methyl-1H-indol-3-ylmethyl)-1-phenylcyclohexane-1,4-di-
amine were also obtained.
Example 34
[0365]
N'-(2-benzo[b]thiophen-3-yl-ethyl)-N,N-dimethyl-1-phenylcyclohexane-
-1,4-diamine dihydrochloride, cis/trans mixture
[0366] Lithium aluminium hydride (1.16 g, 30.3 mmole) was suspended
in dry diethyl ether (100 ml). Anhydrous aluminium chloride (4.04
g, 30.3 mmole) was added under argon to this suspension. After 5
minutes a solution of benzo[b]thiophene-3-acetonitrile (5.25 g,
30.3 mmole) in dry diethyl ether (70 ml) was added. After
completion of the addition the mixture was heated for 4 days under
reflux. Further lithium aluminium hydride (930 mg) and aluminium
chloride (500 mg) were added to the reaction mixture and the whole
was heated under reflux for a further 8 hours. For working-up the
reaction mixture was neutralised with an aqueous solution of
potassium/sodium tartrate (80 ml, 20 m %). After the end of the
evolution of gas the phases were separated and the turbid aqueous
phase was suction filtered through a glass frit. The residue on the
frit was washed with ethyl acetate and the clear aqueous phase was
extracted with ethyl acetate (3.times.50 ml). The organic phases
were dried over sodium sulfate, filtered and concentrated by
evaporation. Crude benzo[b]thiophen-3-yl-ethylamine (3.7 g) was
obtained as a reddish-brown oil. Treatment with methanolic
hydrochloric acid afforded a sticky hydrochloride that was
immediately converted into the free base. 794 mg (15%) of
benzo[b]thiophen-3-yl-ethylamine were obtained as a yellow oil,
which was used for the further synthesis.
[0367] Benzo[b]thiophen-3-yl-ethylamine (289 mg, 1.6 mmole) was
dissolved in dry 1,2-dichloroethane (10 ml) under argon and, after
the addition of 4-dimethylamino-4-phenylcyclo-hexanone (354 mg, 1.6
mmole) and sodium sulfate (2 g), was stirred for 1 hour at RT.
Sodium triacetoxy boron hydride (440 mg, 2.0 mmole) was then added
in one portion to the reaction mixture. After 3 days glacial acetic
acid (4 mmole) was then added and the mixture was stirred for a
further 24 hours at RT. For working-up water (20 ml) was added and
the reaction mixture was suction filtered. The solid obtained was
dissolved with 2 M sodium carbonate solution and ethyl acetate. The
organic phase was separated, dried over sodium sulfate, filtered
and concentrated by evaporation. The solid but sticky residue
obtained (213 mg) was dissolved in 2-butanone (5 ml) and ethanolic
HCl (500 .mu.l, 1.5 mmole) was added at RT. After 2 hours the
solution was evaporated to dryness and the residue was suspended in
diethyl ether (5 ml), suction filtered and washed with diethyl
ether (3.times.3 ml). A mixture of cis- and trans-N'-(2-benzo
[b]thiophen-3-yl-ethyl)-N,N-dimethyl-1-phenylcyclohexane-1,4-diamine
dihydrochloride (217 mg, m.p. 164.degree.-167.degree. C.) was
obtained as a beige-brown solid.
Example 35
[0368]
N'-(2-benzo[b]thiophen-3-yl-ethyl)-1-benzyl-N,N-dimethylcyclohexane-
-1,4-diamine dihydrochloride, cis/trans mixture
[0369] Benzo[b]thiophen-3-yl-ethylamine (350 mg, 1.9 mmole) was
dissolved in dry 1,2-dichloroethane (10 ml) under argon and, after
the addition of 4-benzyl-4-dimethylaminocyclo-hexanone (463 mg, 2
mmole), glacial acetic acid (2 mmole) and anhydrous sodium sulfate
(2 g) was stirred for 1 hour at RT. Sodium triacetoxy boron hydride
(550 mg, 2.5 mmole) was then added in one portion and stirred for 4
days at RT. For working-up the reaction mixture was diluted with
1,2-dichloroethane (10 ml) and water (15 ml). The remaining
precipitate was suction filtered (379 mg, m.p.
225.degree.-233.degree. C.). 353 mg of a yellow oil were obtained
by extracting the aqueous phase adjusted to pH 11 with 5 M sodium
hydroxide with ethyl acetate. The crude product (438 mg, viscous
oil) was isolated from both partial amounts by redissolving in
dilute hydrochloric acid, extraction with diethyl ether (2.times.15
ml) followed by adjusting the aqueous phase to pH 11 with 5 M molar
sodium hydroxide as well as extraction with ethyl acetate
(3.times.20 ml). 366 mg of the obtained diastereo isomer mixture
were dissolved in 2-butanone (30 ml) and ethanolic hydrochloric
acid (847 .mu.l, 2.8 mmole) was added at RT. A precipitate formed
that rapidly redissolved and then reprecipitated during the
post-stirring time (4 days at RT). After a further 30 minutes in a
cooling cabinet the precipitate was suction filtered, washed with
cold 2-butanone (3.times.3 ml) and dried. The pale yellow solid
that was obtained was a mixture of cis- and
trans-N'-(2-benzo[b]thiophen-3-yl-ethy-
l)-1-benzyl-N,N-dimethylcyclohexane-1,4-diamine dihydrochloride
(338 mg, m.p. 225.degree.-229.degree. C.).
Example 36
[0370]
N'-acenaphthen-1-yl-N,N-dimethyl-1-phenylcyclohexane-1,4-diamine
dihydrochloride, polar diastereomer
[0371] 339 mg of acenaphthen-1-ylamine and 435 mg of
4-dimethylamino-4-phenylcyclohexanone were dissolved in dry
1,2-dichloroethane (20 ml) under argon. Glacial acetic acid (2
mmole) and 600 mg of sodium triacetoxy boron hydride were added to
this mixture and stirred for 24 hours at RT. For working-up the
reaction mixture was concentrated by evaporation and the residue
was adjusted to pH 11 with 5 M sodium hydroxide. The alkaline phase
was diluted with water (10 ml) and extracted with ethyl acetate
(4.times.20 ml). The combined extracts were dried over sodium
sulfate, filtered and concentrated by evaporation. The crude
product was chromatographed on silica gel with ethyl
acetate/ethanol (1:1). 130 mg of the polar diastereomer of
N'-acenaphthen-1-yl-N,N-dimethyl-1-phenylcyclohexane-1,4-diamine
were obtained as a white solid, from which the corresponding
dihydrochloride was precipitated with 1.85 M ethanolic hydrochloric
acid (0.5 ml) in 2-butanone (5 ml) (151 mg: m.p.
214.degree.-216.degree. C.).
Example 37
[0372]
N'-acenaphthen-1-yl-N,N-dimethyl-1-phenylcyclohexane-1,4-diamine
dihydrochloride, non-polar diastereomer
[0373] As described for Example 36, 250 mg of the non-polar
diastereomer of
N'-acenaphthen-1-yl-N,N-dimethyl-1-phenylcyclohexane-1,4-diamine
were also obtained as a white solid, from which the corresponding
dihydrochloride was precipitated with 1.85 M ethanolic hydrochloric
acid (0.9 ml) in 2-butanone (10 ml) 300 mg; (m.p.
190.degree.-192.degree. C.).
Example 38
[0374]
N'-benzo[b]thiophen-5-yl-1-benzyl-N,N-dimethylcyclohexane-1,4-diami-
ne dihydrochloride, non-polar diastereomer
[0375] 300 mg of 5-aminobenzothiophene and 463 mg of
4-benzyl-4-dimethylaminocyclohexanone were dissolved in dry
1,2-dichloroethane (20 ml) under argon. Glacial acetic acid (2
mmole) and 600 mg of sodium triacetoxy boron hydride were added to
this mixture and stirred for 24 hours at RT. For working-up the
reaction mixture was concentrated by evaporation and the residue
was adjusted to pH 11 with 5 M sodium hydroxide. The alkaline phase
was diluted with water (10 ml) and extracted with ethyl acetate
(6.times.20 ml). The combined extracts were dried over sodium
sulfate, filtered and concentrated by evaporation. The crude
product was chromatographed on silica gel with ethyl
acetate/ethanol (1:1). 520 mg of the non-polar diastereomer of
N'-benzo[b]thiophen-5-yl-1-benzyl-N,N-dimethylcyclohexane-1,4-diamine
were obtained as a white solid, from which the corresponding
dihydrochloride was precipitated with 1.85 M ethanolic hydrochloric
acid (1.93 ml) in 2-butanone (15 ml) (621 mg; m.p.
140.degree.-142.degree. C.).
Example 39
[0376]
N'-benzo[b]thiophen-5-yl-N,N-dimethyl-1-phenylcyclohexane-1,4-diami-
ne hydrochloride, non-polar diastereomer
[0377] 300 mg of 5-aminobenzothiophene and 435 mg of
4-dimethylamino-4-phenylcyclohexanone were dissolved in dry
1,2-dichloroethane (20 ml) under argon. Glacial acetic acid (2
mmole) and 600 mg of sodium triacetoxy boron hydride were added to
this mixture and stirred for 24 hours at RT. For working-up the
reaction mixture was concentrated by evaporation and the residue
was adjusted to pH 11 with 5 M sodium hydroxide. The alkaline phase
was diluted with water (10 ml) and extracted with ethyl acetate
(3.times.20 ml). The combined extracts were dried over sodium
sulfate, filtered and concentrated by evaporation. The crude
product was chromatographed on silica gel with ethyl
acetate/ethanol (1:1). 230 mg of the non-polar diastereomer of
N'-benzo[b]thiophen-5-yl-1-benzyl-N,N-dimethyl-1-phenylcyclohexane-1,4-di-
amine were obtained as a white solid, from which the corresponding
hydrochloride was precipitated with 1.85 M ethanolic hydrochloric
acid (0.54 ml) in 2-butanone (8 ml) (243 mg; m.p.
155.degree.-157.degree. C.).
Example 40
[0378]
N'-benzothiazol-6-yl-N,N-dimethyl-1-phenylcyclohexane-1,4-diamine
dihydrochloride, non-polar diastereomer
[0379] 300 mg of 6-aminobenzothiazole and 435 mg of
4-dimethyl-amino-4-phenylcyclohexanone were dissolved in dry
1,2-dichloroethane (20 ml) under argon. Glacial acetic acid (2
mmole) and 600 mg of sodium triacetoxy boron hydride were added to
this mixture and stirred for 24 hours at RT. For working-up the
reaction mixture was concentrated by evaporation and the residue
was adjusted to pH 11 with 5 M sodium hydroxide. The alkaline phase
was diluted with water (10 ml) and extracted with ethyl acetate
(3.times.20 ml). The combined extracts were dried over sodium
sulfate, filtered and concentrated by evaporation. The crude
product was chromatographed on silica gel with ethyl
acetate/ethanol (1:1). 220 mg of the non-polar diastereomer of
N'-benzothiazol-6-yl-N,N-dimethyl-1-phenylcyclohexane-1,4-diamine
were obtained as a yellow solid, from which the corresponding
dihydrochloride was precipitated with 1.85 M ethanolic hydrochloric
acid (0.83 ml) in 2-butanone (10 ml) (197 mg; m.p.
144.degree.-147.degree. C.).
Example 41
[0380]
N'-benzo[1,2,5]thiadiazol-4-yl-N,N-dimethyl-1-phenylcyclohexane-1,4-
-diamine dihydrochloride, polar diastereomer
[0381] 302 mg of benzo[1,2,5]thiadiazol-4-ylamine and 435 mg of
4-dimethylamino-4-phenylcyclohexanone were dissolved in dry
1,2-dichloroethane (20 ml) under argon. Glacial acetic acid (2
mmole) and 600 mg of sodium triacetoxy boron hydride were added to
this mixture and stirred for 24 hours at RT. For working-up the
reaction mixture was concentrated by evaporation and the residue
was adjusted to pH 11 with 5 M sodium hydroxide. The alkaline phase
was diluted with water (10 ml) and extracted with ethyl acetate
(3.times.20 ml). The combined extracts were dried over sodium
sulfate, filtered and concentrated by evaporation. The crude
product was chromatographed on silica gel with ethyl
acetate/ethanol (1:1). 40 mg of the polar diastereomer of
N'-benzo[1,2,5]thiadiazol-4-yl-N,N-dimethyl-1-phenylcyclohexane-1,4-diami-
ne were obtained as a red solid, from which the corresponding
dihydrochloride was precipitated with 1.85 M ethanolic hydrochloric
acid (0.15 ml) in 2-butanone (2 ml) (35 mg; m.p.
122.degree.-125.degree. C.).
Example 42
[0382]
N'-[2-(1H-indol-3-yl)-1-methylethyl]-N,N-dimethyl-1-phenylcyclohexa-
ne-1,4-diamine dihydrochloride, non-polar diastereomer
[0383] DL-.alpha.-methyltryptamine (3.00 g, 17.2 mmole) was
dissolved in dry 1,2-dichloroethane (10 ml) under argon. After
addition of 4-dimethylamino-4-phenylcyclohexanone (3.70 g) and
glacial acetic acid (1.5 ml) the mixture was stirred for 1 hour at
RT. Sodium triacetoxy boron hydride (4.7 g) was then added and the
suspension was stirred for 4 days at RT. For working-up
1,2-dichloroethane (20 ml) and water (50 ml) were added to the
reaction mixture. The clear phases were separated, and the aqueous
phase was washed with ether (2.times.20 ml) and then made strongly
alkaline with 5 M sodium hydroxide. The aqueous phase was extracted
with ethyl acetate (5.times.30 ml) and the combined extracts were
dried over sodium sulfate, filtered and concentrated by
evaporation. The crude product obtained (5.8 g of beige-brown
solid) was first of all coarsely fractionated on silica gel with
methanol/triethylamine (199:1) and was then once more finely
purified. 1.20 g of the non-polar diastereomer of
N'-[2-(1H-indol-3-yl)-1-methylethyl]-N,N-dimethyl-1-pheny-
lcyclohexane-1,4-diamine were obtained (m.p.
158.degree.-160.degree. C.). The corresponding dihydrochloride was
precipitated from 1 g of this compound with chlorotrimethylsilane
(840 .mu.l) in 2-butanone/acetone (100 ml/30 ml) (977 mg; m.p.
170.degree.-174.degree. C.).
Example 43
[0384]
N'-adamantan-2-yl-N,N-dimethyl-1-phenylcyclohexane-1,4-diamine
dihydrochloride
[0385] 302 mg of 2-adamantylamine and 434 mg of
4-dimethylamino-4-phenylcy- clohexanone were dissolved in dry
tetrahydrofuran (15 ml) and 1,2-dichloroethane (5 ml) under argon.
600 mg of sodium triacetoxy boron hydride were added to this
mixture and stirred for 23 hours at RT. For working-up the reaction
mixture was concentrated by evaporation and the residue was
extracted with 1 M hydrochloric acid (20 ml) and ether (40 ml). The
aqueous phase was washed with ether (2.times.20 ml), made alkaline
with 5 M sodium hydroxide and extracted with ether (3.times.30 ml).
The combined extracts were dried over sodium sulfate, filtered and
concentrated by evaporation. The crude product was chromatographed
on silica gel with ethyl acetate/methanol (4:1). 130 mg of
N'-adamantan-2-yl-N,N-dimethyl-1-phenylcyclohexane-1,4-diamine were
obtained as a beige-coloured solid, from which the corresponding
dihydrochloride was precipitated with 3.3 M phenolic hydrochloric
acid (0.34 ml) in 2-butanone (6 ml), the dihydrochloride
decomposing on heating from 237.degree. C.
Example 44
[0386]
N'-(9-ethyl-9H-carbazol-3-yl)-N,N-dimethyl-1-phenylcyclohexane-1,4--
diamine dihydrochloride, non-polar diastereomer
[0387] 421 mg of 3-amino-9-ethylcarbazole and 435 mg of
4-dimethylamino-4-phenylcyclohexanone were dissolved in dry
1,2-dichloroethane (20 ml) under argon. Glacial acetic acid (2
mmole) and 600 mg of sodium triacetoxy boron hydride were added to
this mixture and stirred for 24 hours at RT. For working-up the
reaction mixture was concentrated by evaporation and the residue
was adjusted to pH 11 with 5 M sodium hydroxide. The alkaline phase
was diluted with water (10 ml) and extracted with ethyl acetate
(3.times.20 ml). The combined extracts were dried over sodium
sulfate, filtered and concentrated by evaporation. The crude
product was chromatographed on silica gel with ethyl
acetate/ethanol (1:1). 288 mg of the non-polar diastereomer of
N'-(9-ethyl-9H-carbazol-3-yl)-N,N-dimethyl-1-phenylcyclohexane-1,4-diamin-
e were obtained as a brown solid, from which the corresponding
dihydrochloride was precipitated with 1.85 M ethanolic hydrochloric
acid (0.95 ml) in 2-butanone (10 ml) (339 mg; m.p.
145.degree.-150.degree. C.).
Example 45
[0388]
N'-(3H-benzotriazol-5-yl)-N,N-dimethyl-1-phenylcyclohexane-1,4-diam-
ine hydrochloride, non-polar diastereomer
[0389] 268 mg of 5-aminobenzotriazole and 435 mg of
4-dimethyl-amino-4-phenylcyclohexanone were dissolved in dry
1,2-dichloroethane (20 ml) under argon. Glacial acetic acid (2
mmole) and 600 mg of sodium triacetoxy boron hydride were added to
this mixture and stirred for 24 hours at RT. For working-up the
reaction mixture was concentrated by evaporation and the residue
was adjusted to pH 11 with 5 M sodium hydroxide. The alkaline phase
was diluted with water (10 ml) and extracted with ethyl acetate
(3.times.20 ml). The combined extracts were dried over sodium
sulfate, filtered and concentrated by evaporation. The crude
product was chromatographed on silica gel with ethyl
acetate/ethanol (1:1). 135 mg of the non-polar diastereomer of
N'-(3H-benzotriazol-5-yl)-N,N-dimethyl-1-phenylcyclohexane-1,4-diamine
were obtained as a white solid, from which the corresponding
hydrochloride was precipitated with 1.85 M ethanolic hydrochloride
(0.54 ml) in 2-butanone (5 ml) (98 mg; m.p. 168.degree.-173.degree.
C.).
Example 46
[0390]
N'-(3H-benzotriazol-5-yl)-N,N-dimethyl-1-phenylcyclohexane-1,4-diam-
ine hydrochloride, polar diastereomer
[0391] As described for Example 45, 122 mg of the polar
diastereomer of
N'-(3H-benzotriazol-5-yl)-N,N-dimethyl-1-phenylcyclohexane-1,4-diamine
were also obtained as a white solid, from which the corresponding
dihydrochloride was precipitated with 1.85 M ethanolic hydrochloric
acid (0.5 ml) in 2-butanone (5 ml) (119 mg; m.p.
185.degree.-189.degree. C.).
Example 47
[0392]
N'-(9H-fluoren-9-yl)-N,N-dimethyl-1-thiophen-2-yl-cyclohexane-1,4-d-
iamine dihydrochloride, cis/trans mixture
[0393] 2-iodothiophene (22.9 g) was dissolved in THF (80 ml) under
argon and 2 M isopropyl magnesium chloride (35.7 ml) in THF was
added within 30 minutes at 0.degree. C. After a reaction time of 1
hour at 3.degree.-5.degree. C.,
8-dimethylamino-1,4-dioxaspiro[4.5]decane-8-carbo- nitrile (10 g)
dissolved in tetrahydrofuran (20 ml) were added and stirred for 20
hours at room temperature. For working-up saturated NH.sub.4Cl
solution (85 ml) was added, the product was extracted with diethyl
ether (3.times.100 ml) and the combined extracts were washed with
water (50 ml) and saturated NaCl solution (50 ml), dried and
concentrated by evaporation. The crude product obtained (21.3 g of
dark brown oil) was dissolved in 2-butanone (140 ml) and converted
with chlorotrimethylsilane (9.1 ml) into the hydrochloride of
dimethyl-(8-thiophen-2-yl-1,4-dioxaspi- ro[4.5]dec-8-yl)-amine
(white solid; 8.74 g).
[0394] Dimethyl-(8-thiophen-2-yl-1,4-dioxaspiro[4.5]dec-8-yl)-amine
hydrochloride (8.68 g) was dissolved in 7.5 M hydrochloric acid (29
ml), stirred for 48 hours at room temperature and then extracted
with diethyl ether (2.times.50 ml). The aqueous phase was adjusted
alkaline with 5 M sodium hydroxide while cooling with ice,
extracted with dichloromethane (3.times.50 ml), dried and
concentrated by evaporation.
4-dimethylamino-4-thiophen-2-yl-cyclohexanone was thus obtained as
a yellow solid (5.66 g; m.p. 108.degree.-110.degree. C.).
[0395] 362 mg of 9-aminofluorene and 434 mg of
4-dimethylamino-4-thiophen-- 2-yl-cyclohexanone were dissolved in
dry 1,2-dichloroethane (10 ml) under argon. Glacial acetic acid (2
mmole) and 600 mg of sodium triacetoxy boron hydride were added to
this mixture and stirred for 24 hours at RT. For working-up the
reaction mixture was concentrated by evaporation and the residue
was adjusted to pH 11 with 5 M sodium hydroxide. The alkaline phase
was diluted with water (10 ml) and extracted with ethyl acetate
(5.times.20 ml). The combined-extracts were dried over sodium
sulfate, filtered and concentrated by evaporation. The crude
product was chromatographed on silica gel with ethyl
acetate/ethanol (1:1). 440 mg of a cis/trans mixture of
N'-(9H-fluoren-9-yl)-N,N-dimethyl-1-thiophen-2-yl--
cyclohexane-1,4-diamine were obtained as a white solid, from which
the corresponding dihydrochloride was precipitated with 1.85 M
ethanolic HCl (1.55 ml) in 2-butanone (10 ml) (460 mg; m.p.
202.degree.-205.degree. C.).
Example 48
[0396] N'-cyclooctyl-N,N-dimethyl-1-phenylcyclohexane-1,4-diamine
dihydrochloride
[0397] 254 mg of cyclooctylamine and 434 mg of
4-dimethylamino-4-phenylcyc- lohexanone were dissolved in dry
tetrahydrofuran (15 ml) and 1,2-dichloroethane (5 ml) under argon.
Glacial acetic acid (120 mg) and 600 mg of sodium triacetoxy boron
hydride were added to this mixture and stirred for 18 hours at RT.
For working-up the reaction mixture was concentrated by evaporation
and the residue was washed with 1 M hydrochloric acid (20 ml) and
with ether (2.times.30 ml). The aqueous phase was adjusted alkaline
with 5 M sodium hydroxide and extracted with ether (3.times.30 ml).
The combined extracts were dried over sodium sulfate, filtered and
concentrated by evaporation. The crude product (515 mg) was
chromatographed on silica gel with methanol. 108 mg of
N'-cyclooctyl-N,N-dimethyl-1-phenylcyclohexane-1,4-diamine were
obtained as a colourless oil, from which the corresponding
dihydrochloride was precipitated with 3.3 M ethanolic HCl (0.25 ml)
in 2-butanone (2 ml) (102 mg; m.p. 247.degree.-249.degree. C.).
Example 49
[0398]
N'-(1H-indol-3-ylmethyl)-N,N-dimethyl-1-phenylcyclohexane-1,4-diami-
ne dihydrochloride, non-polar diastereomer
[0399] 970 mg of C-(1H-indol-3-yl)-methylamine and 1.44 mg of
4-dimethylamino-4-phenylcyclohexanone were dissolved in dry
tetrahydrofuran (15 ml) and 1,2-dichloroethane (50 ml) under argon.
Glacial acetic acid (13.2 mmole) and 1.82 g of sodium triacetoxy
boron hydride were added to this mixture and stirred for 72 hours
at RT. For working-up the reaction mixture was concentrated by
evaporation, and water (20 ml) and ether (30 ml) were added to the
residue and vigorously stirred. The aqueous phase was separated,
washed with ether (2.times.15 ml), adjusted to pH 11 with 5 M
sodium hydroxide and extracted with ethyl acetate (4.times.25 ml).
The combined extracts were dried over sodium sulfate, filtered and
concentrated by evaporation. The crude product (2.11 g) was
chromatographed on silica gel with methanol/triethylamine (199:1).
465 mg of the non-polar diastereomer of N'-(1H-indol-3-ylmethyl)-
-N,N-dimethyl-1-phenylcyclohexane-1,4-diamine were obtained (m.p.
182.degree.-184.degree. C.), from which the corresponding
dihydrochloride was precipitated with chlorotrimethylsilane (443
.mu.l ) in 2-butanone/acetone (20 ml/50 ml) (498 mg; m.p.
164.degree.-168.degree. C.).
Example 50
[0400]
N'-(1H-indol-3-ylmethyl)-N,N-dimethyl-1-phenylcyclohexane-1,4-diami-
ne dihydrochloride, polar diastereomer
[0401] As described for Example 49, 360 mg of the polar
diastereomer of
N'-(1H-indol-3-ylmethyl)-N,N-dimethyl-1-phenylcyclohexane-1,4-diamine
were also obtained, from which the corresponding dihydrochloride
was precipitated with chlorotrimethylsilane (328 .mu.l) in
2-butanone/acetone (10 ml/25 ml) (435 mg; m.p.
185.degree.-188.degree. C.).
Example 51
[0402]
N'-benzo[b]thiophen-3-ylmethyl-N,N-dimethyl-1-phenylcyclohexane-1,4-
-diamine dihydrochloride, non-polar diastereomer
[0403] Benzothiophene-3-carbaldehyde (4.0 g, 24.6 mmole) was
dissolved in a mixture of pyridine (25 ml) and ethanol (25 ml).
Hydroxylamine hydrochloride (3.4 g, 49.2 mmole) was added while
stirring. The mixture was stirred for 30 minutes at RT and then
heated under reflux for 8 hours. A reddish-brown solution was
formed. For working-up the solution was concentration by
evaporation and the residue was freed from remaining pyridine by
distillation with ethanol (3.times.50 ml). Water (50 ml) was added
to the oily residue and stirred vigorously overnight. The pink
solid that was present was suction filtered, washed with water and
dried in vacuo. 4.3 g of benzothiophene-3-carbaldehyde oxime were
obtained (m.p. 87.degree.-89.degree. C.).
[0404] Benzothiophene-3-carbaldehyde oxime (3.96 g, 22.3 mmole) was
dissolved in methanol (100 ml) and 5 M sodium hydroxide (100 ml)
and Devarda's alloy (14.1 g) was added in portions under argon.
This resulted in a heating of the solution and evolution of
hydrogen. The solution was stirred for 16 hours. The solution was
worked up by slowly adding water (100 ml), a vigorous reaction then
occurring once more. The mixture was filtered through celite, the
methanol was removed in vacuo and the remaining aqueous phase was
extracted with diethyl ether (3.times.50 ml). After concentration
by evaporation of the organic phase 1.43 g of
C-benzo[b]thiophen-3-yl-methylamine remained as a green oil. 3.3 M
ethanolic hydrochloric acid (3.6 ml, 12 mmole) was added to a
solution of this amine (1.3 g, 8 mmole) in 2-butanone (5 ml), 1.18
g of C-benzo[b]thiophen-3-yl-methylamine hydrochloride
precipitating as a white crystalline solid with a melting point of
254.degree.-256.degree. C.
[0405] 449 of C-benzo[b]thiophen-3-yl-methylamine and 434 mg of
4-dimethylamino-4-phenylcyclohexanone were dissolved in dry
tetrahydrofuran (20 ml) and 1,2-dichloroethane (7 ml) under argon.
Glacial acetic acid (165 mg) and 825 mg of sodium triacetoxy boron
hydride were added to this mixture and stirred for 41 hours at RT.
For working-up the reaction mixture was concentrated by evaporation
and the residue was washed with 1 M hydrochloric acid (20 ml) and
with ether (2.times.20 ml). The aqueous phase was adjusted to pH
8-9 with 1 M sodium hydroxide and extracted with ether (3.times.20
ml). The combined extracts were dried over sodium sulfate, filtered
and concentrated by evaporation. The yellow, crystalline crude
product (787 mg) was dissolved in methanol (7 ml) for
chromatographic separation, the non-polar diastereomer then
precipitating out. 247 mg of the non-polar diastereomer of
N'-benzo[b]thiophen-3-ylmethyl-N,N-dimethyl-1-phenylcyclohexane-1,4-diami-
ne were obtained as a white solid (m.p. 138.degree.-140.degree.
C.), from which the corresponding dihydrochloride was precipitated
with 3.3 M ethanolic hydrochloric acid (0.8 ml) in 2-butanone (25
ml) (187 mg; m.p. 225.degree.-230.degree. C.).
Example 52
[0406]
N'-benzo[b]thiophen-3-ylmethyl-N,N-dimethyl-1-phenylcyclohexane-1,4-
-diamine dihydrochloride, polar diastereomer
[0407] As described for Example 51, the methanolic solution of the
crude product was chromatographed on silica gel with methanol. 113
mg of the polar diastereomer of
N'-benzo[b]thiophen-3-ylmethyl-N,N-dimethyl-1-pheny-
lcyclohexane-1,4-diamine were obtained as a colourless oil, from
which the corresponding dihydrochloride was precipitated as a white
solid with 3.3 M ethanolic hydrochloric acid (0.28 ml) in
2-butanone (10 ml) (120 mg; m.p. 252.degree.-254.degree. C.).
Example 53
[0408]
N'-anthracen-2-yl-N,N-dimethyl-1-phenylcyclohexane-1,4-diamine
hydrochloride, non-polar diastereomer
[0409] 386 mg 2-aminoanthracene and 434 mg of
4-dimethylamino-4-phenylcycl- ohexanone were dissolved in dry
1,2-dichloroethane (20 ml) under argon. Glacial acetic acid (2
mmole) and 600 mg of sodium triacetoxy boron hydride were added to
this mixture and stirred for 24 hours at RT. For working-up the
reaction mixture was concentrated by evaporation and the residue
was adjusted to pH 11 with 5 M sodium hydroxide and extracted with
ethyl acetate (4.times.20 ml). The combined extracts were dried
over sodium sulfate, filtered and concentrated by evaporation. The
crude product was chromatographed on silica gel with ethyl
acetate/ethanol (1:1). 132 mg of the non-polar diastereomer of
N'-anthracen-2-yl-N,N-dime- thyl-1-phenylcyclohexane-1,4-diamine
were obtained as a green solid, from which the corresponding
hydrochloride was precipitated with 1.85 M ethanolic HCl (0.46 ml)
in 2-butanone (5 ml) (104 mg; m.p. 169.degree.-172.degree. C.).
Example 54
[0410]
N'-benzo[b]thiophen-3-ylmethyl-1-benzyl-N,N-dimethylcyclohexane-1,4-
-diamine dihydrochloride, non-polar diastereomer
[0411] 391 mg of C-benzo[b]thiophen-3-yl-methylamine and 554 mg of
4-dimethylaminocyclohexanone were dissolved in dry tetrahydrofuran
(18 ml) and 1,2-dichloroethane (6 ml) under argon. Glacial acetic
acid (144 mg) and 720 mg of sodium triacetoxy boron hydride were
added to this mixture and stirred for 22 hours at RT. For
working-up the reaction mixture was concentrated by evaporation and
the residue was taken up in 1 M hydrochloric acid (20 ml) and
washed with ether (2.times.20 ml). The aqueous phase was adjusted
to pH 8-9 with 1 M sodium hydroxide and extracted with ether
(3.times.20 ml). The combined extracts were dried over sodium
sulfate, filtered and concentrated by evaporation. The pale yellow
oil that was obtained (904 mg) was chromatographed on silica gel
with methanol. 368 mg of the non-polar diastereomer of
N'-benzo[b]thiophen-3-ylmethyl-1-benzyl-N,N-dimethylcyclohexane-1,4-diami-
ne were obtained, from which the corresponding dihydrochloride was
precipitated with 3.3 M ethanolic hydrochloric acid (0.88 ml) in
2-butanone (25 ml) (364 mg; m.p. 246.degree.-255.degree. C.).
Example 55
[0412]
N'-benzo[b]thiophen-3-ylmethyl-1-benzyl-N,N-dimethylcyclohexane-1,4-
-diamine dihydrochloride, polar diastereomer
[0413] As described for Example 54, 347 mg of the polar
diastereomer of
N'-benzo[b]thiophen-3-ylmethyl-1-benzyl-N,N-dimethylcyclohexane-1,4-diami-
ne were obtained, from which the corresponding dihydrochloride was
precipitated with 3.3 M ethanolic hydrochloric acid (0.83 ml) in
2-butanone (25 ml) (418 mg; m.p. 242.degree.-248.degree. C.).
Example 56
[0414]
N'-[2-(1H-indol-3-yl)-ethyl]-N,N-dimethyl-1-naphthalen-2-yl-cyclohe-
xane-1,4-diamine dihydrochloride, non-polar diastereomer
[0415] A Grignard solution was prepared from magnesium (2.05 g) and
2-bromonaphthalene (17.7 g) in dry tetrahydrofuran (65 ml). This
Grignard solution was stirred for 1 hour at the boiling point.
8-dimethylamino-1,4-dioxaspiro[4.5]-decane-8-carbonitrile (9.0 g)
dissolved in dry tetrahydrofuran (70 ml) was then added dropwise at
RT and stirred overnight at RT. After completion of the reaction
the mixture was quenched with saturated ammonium chloride solution
while cooling with ice, and was extracted with diethyl ether
(2.times.70 ml), dried over sodium sulfate and concentrated by
evaporation. For purification the crude product (24.2 g) was
dissolved in 2-butanone (130 ml) and Me.sub.3SiCl (14.8 ml) was
added while cooling with ice. After 6 hours the precipitated
dimethyl-(8-naphthalen-2-yl-1,4-dioxaspiro-[4.5]dec-8-yl- )-amine
was filtered under suction (white solid; 6.09 g).
[0416]
Dimethyl-(8-naphthalen-2-yl-1,4-dioxaspiro[4.5]dec-8-yl)-amine
hydrochloride (6.09 g) was dissolved in 7.5 N hydrochloric acid,
stirred for 32 hours at RT and then extracted with diethyl ether
(3.times.30 ml). The aqueous phase was adjusted alkaline with 25%
ammonia solution while cooling in ice and extracted with
1,2-dichloroethane (3.times.30 ml). The combined extracts were
dried over sodium sulfate and concentrated by evaporation. 4.48 g
of 4-dimethylamino-4-naphthalen-2-yl-cyclohexanone were obtained as
a white solid (m.p. 81.degree.-83.degree. C.)
[0417] The dihydrochloride of the non-polar diastereomer of
N'-[2-(1H-indol-3-yl)-ethyl]-N,N-dimethyl-1-naphthalen-2-yl-cyclohexane-1-
,4-diamine was obtained similarly to the examples described above
by reductive amination of
4-dimethylamino-4-naphthalen-2-yl-cyclohexanone with
tryptamine.
Example 57
[0418]
N'-[2-(1H-indol-3-yl)-ethyl]-N,N-dimethyl-1-phenylcyclohexane-1,4-d-
iamine dihydrochloride, non-polar diastereomer
[0419] 1.12 g of tryptamine and 1.52 g of
4-dimethylamino-4-phenylcyclohex- anone were dissolved in dry
tetrahydrofuran (12 ml) and 1,2-dichloroethane (40 ml) under argon.
Glacial acetic acid (801 .mu.l) and 1.92 g of sodium triacetoxy
boron hydride were added to this mixture and stirred for 4 days at
RT. For working-up the reaction mixture was concentrated by
evaporation and the residue was taken up in water (20 ml), 2 M
hydrochloric acid (5 ml) and ether (35 ml). The aqueous phase was
separated, washed with ether (2.times.15 ml), adjusted to pH 11
with sodium hydroxide and extracted with ethyl acetate (3.times.20
ml). The combined extracts were dried over sodium sulfate, filtered
and concentrated by evaporation. The beige-brown residue that was
obtained (2.0 g) was chromatographed on silica gel with methanol
containing 0.75 vol. % of triethylamine. 553 mg of the non-polar
diastereomer of
N'-[2-(1H-indol-3-yl)-ethyl]-N,N-dimethyl-1-phenylcyclohexane-1,4-diamine
were obtained (m.p. 175.degree.-178.degree. C.), from which the
corresponding dihydrochloride was obtained with
chlorotrimethylsilane in 2-butanone/acetone (20 ml/50 ml) (600 mg;
m.p. 216.degree.-218.degree. C.).
Example 58
[0420]
N'-[2-(1H-indol-3-yl)-ethyl]-N,N-dimethyl-1-phenylcyclohexane-1,4-d-
iamine dihydrochloride, polar diastereomer
[0421] As described for Example 57, 546 mg of the polar
diastereomer of
N'-[2-(1H-indol-3-yl)-ethyl]-N,N-dimethyl-1-phenylcyclohexane-1,4-diamine
were also obtained (m.p. 175.degree.-180.degree. C.), from which
the corresponding dihydrochloride was obtained with
chlorotrimethylsilane (573 .mu.l) in 2-butanone/acetone (3 ml/30
ml) (520 mg; m.p. 223.degree.-229.degree. C.).
Example 59
[0422]
N'-[2-(1H-indol-3-yl)-1-methylethyl]-N,N-dimethyl-1-phenylcyclohexa-
ne-1,4-diamine dihydrochloride, polar diastereomer
[0423] As described for Example 42, 546 mg of the polar
diastereomer of
N'-[2-(1H-indol-3-yl)-1-methylethyl]-N,N-dimethyl-1-phenylcyclohexane-1,4-
-diamine were also obtained (m.p. 50.degree.-55.degree. C.), from
which the corresponding dihydrochloride was obtained as a pale pink
solid with chlorotrimethylsilane (1.0 ml) in 2-butanone (50 ml)
(1.1 mg; m.p. 194.degree.-199.degree. C.).
Example 60
[0424] Methyl
2-(4-dimethylamino-4-phenylcyclohexylamino)-3-(1H-indol-3-yl-
)-propionate dihydrochloride, non-polar diastereomer
[0425] 4-dimethylamino-4-phenylcyclohexanone (435 mg, 2 mmole),
glacial acetic acid (57 .mu.l, 1 mmole) and fused sodium sulfate (2
g) were added to L-tryptophan methyl ester (438 mg, 2 mmole) in
1,2-dichloroethane (20 ml). After stirring for 2 hours at RT sodium
triacetoxy boron hydride (660 mg, 3 mmole) was added and stirring
was continued. After 3 days the reaction mixture was concentrated
by evaporation and the residue was suspended in diethyl ether (20
ml) and 1 M NaOH (5 ml). After the extraction of the aqueous phase
with dietheyl ether and ethyl acetate (each 3.times.10 ml) the
combined organic phases were then washed twice in a separating
funnel with 1 M NaOH (5 ml), dried and concentrated by evaporation.
The viscous residue (718 mg) was purified twice by flash
chromatography [50 kg silica gel, eluent: ethyl acetate/methanol
(3:1) as well as ethyl acetate/MeOH (1:1)] and in this way the
diastereomers were separated. 270 mg of the non-polar diastereomer
of methyl
2-(4-dimethylamino-4-phenylcyclohexylamino)-3-(1H-indol-3-yl)-propionate
were obtained, from which the corresponding dihydrochloride was
obtained as a white solid with chlorotrimethylsilane (244 .mu.l) in
2-butanone/acetone (8 ml/4ml) (291 mg, m.p. 175.degree.-180.degree.
C.).
Example 61
[0426] Methyl
2-(4-dimethylamino-4-phenylcyclohexylamino)-3-(1H-indol-3-yl-
)-propionate dihydrochloride, polar diastereomer
[0427] As described for Example 60, the polar diastereomer of
methyl
2-(4-dimethylamino-4-phenylcyclohexylamino)-3-(1H-indol-3-yl)-propionate
was also obtained (140 mg, m.p. 60.degree.-65.degree. C.), from
which the corresponding dihydrochloride was obtained as a white
solid with chlorotrimethylsilane (126 .mu.l) in 2-butanone/acetone
(7 ml/3 ml) (129 mg; m.p. 180.degree.-185.degree. C.).
Example 62
[0428]
N'-[2-(1H-indol-3-yl)-1-methylethyl]-N,N-dimethyl-1-naphthalen-2-yl-
-cyclohexane-1,4-diamine dihydrochloride, non-polar
diastereomer
[0429] 4-dimethylamino-4-naphthalen-2-yl-cyclohexanone (534 mg) and
DL-.alpha.-methyltryptamine (348 mg) were dissolved in a mixture of
tetrahydrofuran (20 ml) and 1,2-dichloroethane (5 ml) under argon.
Glacial acetic acid (120 mg) was added thereto and, after a
reaction time of 15 minutes, sodium triacetoxy boron hydride (600
mg) was also added. After 64 hours the reaction mixture was suction
filtered. After taking up the white solid obtained in 1 M sodium
hydroxide (20 ml), extraction with diethyl ether (3.times.20 ml)
and concentrating by evaporation the dried combined extracts, an
oily residue (520 mg) was obtained. The chromatographic separation
of the mixture was carried out first of all with methanol, 295 mg
(m.p. 68.degree.-70.degree. C.) of the non-polar diastereomer being
obtained as a white solid. The non-polar diamine was dissolved in
2-butanone (5 ml) and 3.3 N ethanolic hydrochloric acid (0.52 ml)
was added, an oily solid precipitating out. After concentrating by
evaporation the reaction mixture and adding diethyl ether the
crystalline dihydrochloride of the non-polar diastereomer of
N'-[2-(1H-indol-3-yl)-1-methylethyl]-N,N-dimethyl-1-naphthalen-2-yl-cyclo-
hexane-1,4-diamine was obtained (319 mg; m.p.
206.degree.-210.degree. C.).
Example 63
[0430]
N'-benzo[1,3]dioxol-5-ylmethyl-N,N-dimethyl-1-phenylcyclohexane-1,4-
-diamine dihydrochloride, cis/trans mixture
[0431] 3,4-(methylenedioxy)benzylamine (250 .mu.l) and
4-dimethylamino-4-phenylcyclohexanone (434 mg) were dissolved in
dry 1,2-dichloroethane (10 ml) with the exclusion of oxygen.
Glacial acetic acid (2 mmole) and sodium triacetoxy boron hydride
(600 mg) were added to this mixture. The mixture was then stirred
for 24 hours at RT. The mixture was worked up by concentration by
evaporation, adjusting to pH 11 with 5 M NaOH, diluting with water
(10 ml) and extracting with ethyl acetate (4.times.20 ml). The
combined organic extracts were dried over sodium sulfate and
concentrated by evaporation. The colourless oil obtained (795 mg)
was dissolved in 2-butanone (13 ml) and the dihydrochloride of
N'-benzo[1,3]dioxol-5-ylmethyl-N,N-dimethyl-1-phenylcy-
clohexane-1,4-diamine was obtained as a mixture of the cis/trans
isomers with chlorotrimethylsilane (718 .mu.l) (white solid; 790
mg; m.p. 128.degree.-131.degree. C.).
Example 64
[0432]
N'-[2-(6-fluoro-1H-indol-3-yl)-ethyl]-N,N-dimethyl-1-phenylcyclohex-
ane-1,4-diamine dihydrochloride, non-polar diastereomer
[0433] 6-fluorotryptamine (410 mg) and
4-dimethylamino-4-phenylcyclohexano- ne (545 mg) were dissolved in
THF (18 ml) and 1,2-dichloroethane (6 ml) under argon and glacial
acetic acid (138 mg) was added. After 15 minutes sodium triacetoxy
boron hydride (600 mg) and THF (5 ml) were added. After 40 hours
the reaction mixture was concentrated by evaporation and the
residue was taken up in 1 M hydrochloric acid (20 ml) and extracted
with ether (2.times.20 ml). The aqueous phase was adjusted alkaline
with 1 M sodium hydroxide (30 ml) and extracted with ether
(3.times.30 ml). A white solid (785 mg) precipitated out between
the phases and was separated. The white solid was a mixture of the
two diastereomers, which also occurred when concentrating by
evaporation the ethereal phase. The mixtures (985 mg) were
separated jointly by column chromatography with methanol/conc.
ammonia (500:1). The non-polar diastereomer was obtained as a white
solid (321 mg, m.p. 185.degree.-187.degree. C.), dissolved in
ethanol (20 ml) by heating, following which 3.3 N ethanolic HCl
(0.79 ml) was added. After stirring for 1 hour at RT the white
dihydrochloride of the non-polar diamine of
N'-[2-(6-fluoro-1H-indol-3-yl)-ethyl]-N,N-dimeth-
yl-1-phenylcyclohexane-1,4-diamine was obtained (344 mg; m.p.
190.degree.-195.degree. C.).
Example 65
[0434]
N'-[2-(6-fluoro-1H-indol-3-yl)-ethyl]-N,N-dimethyl-1-phenylcyclohex-
ane-1,4-diamine dihydrochloride, polar diastereomer
[0435] As described for Example 64, 305 mg of the polar
diastereomer of
N'-[2-(6-fluoro-1H-indol-3-yl)-ethyl]-N,N-dimethyl-1-phenylcyclohexane-1,-
4-diamine were also obtained, from which the corresponding
dihydrochloride was obtained with 3.3 M ethanolic HCl (0.73 ml) in
ethanol (20 ml) (270 mg; m.p. 208.degree.-211.degree. C.).
Example 66
[0436]
N'-[2-(1H-indol-3-yl)-ethyl]-N,N,N'-trimethyl-1-phenylcyclohexane-1-
,4-diamine dihydrochloride, non-polar diastereomer
[0437] N-.omega.-methyltryptamine
([2-(1H-indol-3-yl)-ethyl]methylamine, 348 mg) was dissolved in dry
1,2-dichloroethane (10 ml) under argon. After addition of
4-dimethylamino-4-phenylcyclohexanone (435 mg) and glacial acetic
acid (114 .mu.l) a voluminous precipitate formed. The suspension
was stirred for 2 hours at RT before adding sodium triacetoxy boron
hydride (660 mg). The reaction mixture was stirred for 2 days at
RT, worked up by concentration by evaporation, the residue was
dissolved in water (15 ml) and diethyl ether (20 ml) and the
organic phase was separated. The aqueous phase was extracted with
diethyl ether (2.times.10 ml) and adjusted to pH 10 with 1 M NaOH.
A white solid precipitated out, which was suction filtered, washed
and dried (174 mg, m.p. 208.degree.-210.degree. C., non-polar
diastereomer). The aqueous phase was adjusted to pH 11 with 1 M
NaOH and extracted with ethyl acetate (4.times.25 ml). The extracts
were combined, dried over sodium sulfate and concentrated by
evaporation in vacuo. The residue (469 mg) was separated by flash
chromatography with methanol/triethylamine (99:1). The non-polar
diastereomer that was thus obtained (172 mg) was dissolved hot in
2-butanone/acetone (15 ml/15 ml) and the hydrochloride of
N'-[2-(1H-indol-3-yl)-ethyl]-N,N,N'-trimethyl-1-phenylcyclohexane-1,4-dia-
mine was precipitated as a white solid at RT with
chlorotrimethylsilane (174 .mu.l) (173 mg; m.p.
195.degree.-198.degree. C.).
Example 67
[0438]
N'-[2-(1H-indol-3-yl)-ethyl]-N,N,N'-trimethyl-1-phenylcyclohexane-1-
,4-diamine dihydrochloride, polar diastereomer
[0439] As described for Example 66, 129 mg of the polar
diastereomer of
N'-[2-(1H-indol-3-yl)-ethyl]-N,N,N'-trimethyl-1-phenylcyclohexane-1,4-dia-
mine were also obtained, which was converted into the corresponding
dihydrochloride by heating in 2-butanone/acetone (15 ml/3 ml) with
chlorotrimethylsilane (121 .mu.l) (white solid; 141 mg; m.p.
198.degree.-206.degree. C.).
Example 68
[0440]
N,N-dimethyl-N'-[2-(7-methyl-1H-indol-3-yl)-ethyl]-1-phenylcyclohex-
ane-1,4-diamine dihydrochloride, non-polar diastereomer
[0441] 7-methyltryptamine (348 mg) and
4-dimethylamino-4-phenylcyclohexano- ne (435 mg) were dissolved in
dry 1,2-dichloroethane (5 ml) and tetrahydrofuran (15 ml) with the
exclusion of oxygen. Glacial acetic acid (2 mmole) and sodium
triacetoxy boron hydride (600 mg) were added to this mixture and
stirred for 24 hours at RT. For working-up the reaction mixture was
concentrated by evaporation, 1 M HCl (20 ml) and diethyl ether (40
ml) were added thereto, and the acidic aqueous phase was extracted
with diethyl ether (2.times.20 ml) and adjusted to pH 11 with 5 M
NaOH. The alkaline phase was diluted with water (10 ml) and
extracted with ethyl acetate (3.times.20 ml). The combined extracts
were dried over sodium sulfate, concentrated by evaporation and the
crude product obtained was separated on silica gel with
EtOH/NH.sub.3 (500:1). The non-polar diastereomer was obtained as a
brown oil (321 mg), dissolved in 2-butanone (10 ml) and converted
into the dichloride with chlorotrimethyl-silane (270 .mu.l) (white
solid; 420 mg; m.p. 189.degree.-191.degree. C.).
Example 69
[0442]
N,N-dimethyl-N'-[2-(7-methyl-1H-indol-3-yl)-ethyl]-1-phenylcyclohex-
ane-1,4-diamine dihydrochloride, polar diastereomer
[0443] As described for Example 68, 144 mg of the polar
diastereomer were also obtained as a brown oil, dissolved in
2-butanone (5 ml) and converted into the corresponding
hydrochloride with chlorotrimethylsilane (121 .mu.l) (white solid;
146 mg; m.p. 244.degree.-246.degree. C.).
Example 70
[0444]
N'-[2-(5-fluoro-1H-indol-3-yl)-ethyl]-N,N-dimethyl-1-phenylcyclohex-
ane-1,4-diamine dihydrochloride, non-polar diastereomer
[0445] 2-(5-fluoro-1H-indol-3-yl)ethylamine (282 mg) and
4-dimethylamino-4-phenylcyclohexanone (343 mg) were first of all
added to a mixture of tetrahydrofuran (12 ml) and
1,2-dichloromethane (4 ml) under argon, following which glacial
acetic acid (0.09 ml) was added. After 15 minutes NaBH(OAc).sub.3
(474 mg) was added and stirred for 40 hours at RT. The reaction
mixture was concentrated by evaporation and the residue was taken
up in 1 M hydrochloric acid (20 ml) and extracted with ether
(2.times.30 ml). A white precipitate formed (191 mg), which was
separated. The aqueous solution was then adjusted alkaline with 1 M
NaOH (28 ml) and extracted with ether (2.times.30 ml) and ethyl
acetate (2.times.30 ml). The combined organic extracts were dried
over sodium sulfate and concentrated by evaporation. The residue
(468 mg) consisted, just like the previously separated solid, of
two products. The combined products (459 mg) were purified by
column chromatography with methanol/ammonia (500:1). The non-polar
diastereomer was obtained as a white solid (218 mg; m.p.
191.degree.-192.degree. C.), dissolved in ethanol (15 ml) by
heating, following which 3.3 N ethanolic hydrochloric acid (0.47
ml, 1.56 mmole) was added. Since after 90 minutes no solid had yet
precipitated, 2-butanone (5 ml) was added. After a short time
crystallisation of the hydrochloride then began (184 mg; m.p.
230.degree.-237.degree. C.).
Example 71
[0446]
N'-[2-(5-fluoro-1H-indol-3-yl)-ethyl]-N,N-dimethyl-1-phenylcyclohex-
ane-1,4-diamine dihydrochloride, polar diastereomer
[0447] As described for Example 70, the polar diastereomer was also
obtained (189 mg; m.p. 200.degree.-201.degree. C.), 159 mg of which
were dissolved in ethanol (15 ml) and 2-butanone (5 ml) and
converted into the dihydrochloride with 3.3 N ethanolic
hydrochloride (0.38 ml) (124 mg; m.p. 262.degree.-265.degree.
C.).
Example 72
[0448]
N'-acenaphthen-5-ylmethyl-N,N-dimethyl-1-phenylcyclohexane-1,4-diam-
ine dihydrochloride, non-polar diastereomer
[0449] Acenaphthen-5-ylmethylamine (366 mg) and
4-dimethylamino-4-phenylcy- clohexanone (434 mg) were dissolved in
dry 1,2-dichloroethane (10 ml) with the exclusion of oxygen.
Glacial acetic acid (2 mmole) and sodium triacetoxy boron hydride
(600 mg) were added to this mixture and stirred for 24 hours at RT.
For working-up the reaction mixture was concentrated by evaporation
and the residue was adjusted to pH 11 with 5 M NaOH. The alkaline
phase was diluted with water (10 ml) and extracted with ethyl
acetate (3.times.20 ml). The combined organic phases were dried
over sodium sulfate and concentrated by evaporation. The crude
product obtained was purified by chromatography with ethyl
acetate/EtOH (1:1). The non-polar diastereomer was obtained as a
colourless oil (330 mg), dissolved in 2-butanone (10 ml) and
converted into the corresponding dihydrochloride with
chlorotrimethylsilane (272 .mu.l) (white solid; 393 mg; m.p.
164.degree.-167.degree. C.).
Example 73
[0450]
N'-[2-(1H-indol-3-yl)-1-methylethyl]-N,N-dimethyl-1-thiophen-2-yl-c-
yclohexane-1,4-diamine dihydrochloride, non-polar diastereomer
[0451] DL-.alpha.-methyltryptamine
(N'-[2-(1H-indol-3-yl)-1-methylethyl]-N-
,N-dimethyl-1-thiophen-2-yl-cyclohexane-1,4-diamine, 348 mg) were
dissolved in dry 1,2-dichloroethane (20 ml) under argon. After
addition of 4-dimethylamino-4-thiophen-2-yl-cyclohexanone (447 mg)
and glacial acetic acid (114 .mu.l) a voluminous precipitate
formed. The suspension was stirred for 1 hour at RT. Sodium
triacetoxy boron hydride (660 mg) was then added and the reaction
mixture was stirred for 2 days at RT. For working-up the mixture
was diluted with 1,2-dichloroethane (10 ml) and water (15 ml), the
organic phase was separated, and the aqueous phase was extracted
once more with 1,2-dichloroethane (2.times.5 ml), adjusted alkaline
with 5 M NaOH and extracted with ethyl acetate (4.times.15 ml). The
combined organic phases were dried, concentrated by evaporation and
purified by flash chromatography (50 g silica gel 60, eluent:
methanol/NEt.sub.3 (99:1)). The non-polar diastereomer (202 mg,
m.p. 158.degree.-161.degree. C.) was dissolved in 2-butanone (5 ml)
and converted into the corresponding dihydrochloride with
chlorotrimethylsilane (202 .mu.l) (white solid, 207 mg; m.p.
162.degree.-165.degree. C.).
Example 74
[0452]
N'-[2-(1H-indol-3-yl)-1-methylethyl]-N,N-dimethyl-1-thiophen-2-yl-c-
yclohexane-1,4-diamine dihydrochloride, cis/trans mixture
[0453] As described for Example 73, a mixture of the diastereomers
(195 mg) was also isolated, dissolved in 2-butanone (4 ml) and
converted into the corresponding dihydrochloride with
chlorotrimethylsilane (194 .mu.l) (white solid; 232 mg;
polar/non-polar=70:30).
Example 75
[0454]
N'-[2-(7-benzyloxy-1H-indol-3-yl)-ethyl]-N,N-dimethyl-1-phenylcyclo-
hexane-1,4-diamine dihydrochloride, non-polar diastereomer
[0455] 7-benzyloxytryptamine (200 mg) was dissolved in dry
1,2-dichloroethane (10 ml) and THF (10 ml) under argon. After
addition of 4-dimethylamino-4-phenylcyclohexanone (180 mg) and
glacial acetic acid (43 .mu.l) the mixture was stirred for 1 hour
at RT following which sodium triacetoxy boron hydride (248 mg) was
added. The reaction mixture was stirred for 3 days at RT. For
working-up the reaction mixture was concentrated by evaporation,
the residue was dissolved in water (15 ml), 2 M HCl (2 ml) and
diethyl ether (20 ml), the organic phase was separated, and the
aqueous phase was washed with diethyl ether (2.times.15 ml),
adjusted to pH 11 with 1 M NaOH and extracted with ethyl acetate
(4.times.10 ml). The combined ethyl acetate extracts were dried,
concentrated by evaporation and the residue obtained (351 mg) was
purified by flash chromatography (45 g silica gel 60, eluent:
MeOH/NEt.sub.3 (99:1)). The non-polar diastereomer (188 mg) was
dissolved hot in 2-butanone/acetone (6 ml/6 ml) and converted into
the corresponding dihydrochloride with chlorotrimethylsilane (147
.mu.l) (white solid, 176 mg; m.p. 162.degree.-166.degree. C.).
Example 76
[0456]
N'-cyclooctyl-N,N-dimethyl-1-thiophen-2-yl-cyclohexane-1,4-diamine
dihydrochloride, non-polar diastereomer
[0457] 4-dimethylamino-4-phenylcyclohexanone (447 mg, 2 mmole) was
dissolved in 1,2-dichloroethane (25 ml) under argon, followed by
the addition of cyclooctylamine (254 mg) and glacial acetic acid
(120 mg). The mixture was stirred for 15 minutes at RT and sodium
triacetoxy boron hydride (600 mg) was then added. After 48 hours at
RT the reaction mixture was concentrated by evaporation on a rotary
evaporator, and the residue was taken up in 1 M HCl (20 ml) and
washed with diethyl ether (2.times.30 ml). The aqueous solution was
then adjusted alkaline with 1 M NaOH (28 ml) and extracted with
Et.sub.2O (3.times.30 ml). The combined organic extracts were dried
over sodium sulfate and concentrated by evaporation. The oily
residue (586 mg) was purified chromatographically with
methanol/ammonia (500:1). The non-polar product was a colourless
oil (280 mg) and was dissolved in 2-butanone (20 ml) and converted
into the corresponding dihydrochloride with 3.3 N ethanolic
hydrochloric acid (0.76 ml) (white solid; 273 mg; m.p.
205.degree.-207.degree. C.).
Example 77
[0458]
N'-adamantan-2-yl-N,N-dimethyl-1-thiophen-2-yl-cyclohexane-1,4-diam-
ine dihydrochloride, non-polar diastereomer
[0459] 2-adamantylamine (302 mg) and
4-dimethylamino-4-phenylcyclohexanone (446 mg) were dissolved under
argon in a mixture of THF (15 ml) and 1,2-dichloroethane (5 ml).
After 15 minutes sodium triacetoxy boron hydride (600 mg) was added
to the mixture and the whole was stirred for 45 hours at room
temperature. For working-up the reaction mixture was concentrated
by evaporation, the residue was taken up in 1 M HCl (20 ml) and
diethyl ether (40 ml), the phases were separated, and the aqueous
phase was washed with diethyl ether (2.times.30 ml). The aqueous
phase was adjusted alkaline with 5 M sodium hydroxide and extracted
with diethyl ether (3.times.30 ml). After concentrating by
evaporation the combined organic extracts the crude product
obtained was separated chromatographically with methanol. The
non-polar diastereomer (286 mg) was dissolved in 2-butanone (15 ml)
and converted into the corresponding dihydrochloride with 3.3 N
ethanolic hydrochloric acid (0.606 ml) (white solid; 300 mg; m.p.
266.degree.).
Example 78
[0460]
3-[2-(4-dimethylamino-4-phenylcyclohexyl-amino)-ethyl]-1H-indol-5-o-
l dihydrochloride, non-polar diastereomer
[0461] Serotonin (405 mg) was dissolved in 1,2-dichloroethane/THF
(5 ml/20 ml), followed by the addition of
4-dimethylamino-4-phenylcyclohexanone (500 mg), glacial acetic acid
(131 .mu.l) and fused sodium sulfate (2 g). After stirring for 1
hour at RT sodium triacetoxy boron hydride (759 mg) was added and
the mixture was stirred for a further 2 days. For working-up the
reaction mixture was concentrated by evaporation, the residue was
suspended in diethyl ether (15 ml), water (10 ml) and 2 M HCl (1
ml), further diethyl ether (20 ml) was added, and the organic phase
was coarsely separated. The aqueous phase was first of all adjusted
to pH 9 with 1 M NaOH and extracted with ethyl acetate (3.times.5
ml), and then adjusted to pH 11 and re-extracted with ethyl acetate
(5.times.10 ml). The organic extracts were dried, concentrated by
evaporation and purified by flash chromatography (eluent:
MeOH/NEt.sub.3 (99.5:0.5)). 267 mg of the non-polar diastereomer
were isolated (m.p. 90.degree.-100.degree. C.), which was dissolved
in ethanol/2-butanone (3 ml/15 ml) and converted into the
corresponding dihydrochloride with 3.3 M ethanolic HCl (642 .mu.l)
(white solid; 304 mg; m.p. 215.degree.-217.degree. C.).
Example 79
[0462]
3-[2-(4-dimethylamino-4-phenylcyclohexyl-amino)-ethyl]-1H-indol-5-o-
l dihydrochloride, polar diastereomer
[0463] As described for Example 78, 124 mg of the polar
diastereomer were also obtained (m.p. 185.degree.-187.degree. C.),
dissolved in ethanol/2-butanone (6 ml/15 ml) and converted into the
corresponding dihydrochloride with 3.3 N ethanolic HCl (298 .mu.l)
(white solid; 123 mg; m.p. 230.degree.-233.degree. C.).
Example 80
[0464]
N'-[2-(5-methoxy-1H-indol-3-yl)-ethyl]-N,N-dimethyl-1-phenylcyclohe-
xane-1,4-diamine dihydrochloride, non-polar diastereomer
[0465] 6-methoxytryptamine (495 mg) was dissolved in dry
1,2-dichloroethane and THF (5 ml/15 ml) under argon to form a clear
solution. After addition of 4-dimethylamino-4-phenylcyclohexanone
(565 mg) and glacial acetic acid (148 .mu.l) the mixture was
stirred for 2 hours at RT, before adding sodium triacetoxy boron
hydride (858 mg). The reaction mixture was stirred for 2 days at
RT. For working-up water (15 ml) and 5.5 M HCl (1.5 ml) were added
to the reaction mixture. The phases were separated, the aqueous
phase (pH 3) was washed with diethyl ether (3.times.10 ml), and
then adjusted to pH 11 with 1 M NaOH and extracted with ethyl
acetate (5.times.15 ml). The combined extracts were dried over
sodium sulfate and concentrated by evaporation. The remaining
residue (1.0 g; m.p. 129.degree.-153.degree. C.) was purified by
flash chromatography (eluent: MeOH/NEt.sub.3 (99.25:0.75)). The
non-polar diastereomer (550 mg, m.p. 164.degree.-169.degree. C.)
was separated cleanly, dissolved hot in 2-butanone/acetone (15
ml/16 ml) and converted into the corresponding dihydrochloride with
chlorotrimethylsilane (533 .mu.l) (white solid; 633 mg; m.p.
165.degree.-175.degree. C.).
Example 81
[0466]
N'-[2-(5-methoxy-1H-indol-3-yl)-ethyl]-N,N-dimethyl-1-phenylcyclohe-
xane-1,4-diamine dihydrochloride, polar diastereomer
[0467] As described for Example 80, the polar diastereomer (320 mg;
m.p. 136.degree.-140.degree. C.) was also obtained, dissolved in
2-butanone/acetone (15 ml/3 ml) and converted into the
corresponding dihydrochloride with chlorotrimethylsilane (310
.mu.l) (white solid; 362 mg; m.p. 206.degree.-210.degree. C.).
Example 82
[0468]
N,N-dimethyl-N'-[2-(5-methyl-1H-indol-3-yl)-ethyl]-1-phenylcyclohex-
ane-1,4-diamine dihydrochloride, non-polar diastereomer
[0469] 5-methyltryptamine (348 mg) and
4-dimethylamino-4-phenylcyclohexano- ne (435 mg) were dissolved in
dry 1,2-dichloroethane (5 ml) and tetrahydrofuran (15 ml) with the
exclusion of oxygen. Glacial acetic acid (114 .mu.l) and sodium
triacetoxy boron hydride (600 mg) were added to this mixture and
the whole was stirred for 24 hours at RT. For working-up the
reaction mixture was concentrated by evaporation, the residue was
taken up in 1 M HCl (20 ml) and diethyl ether (40 ml), the phases
were separated, and the aqueous phase was extracted with diethyl
ether (2.times.20 ml) and adjusted to pH 11 with 5 M NaOH. The
aqueous phase was diluted with water (10 ml) and extracted with
ethyl acetate (3.times.20 ml). The combined organic extracts were
dried over sodium sulfate and concentrated by evaporation. The
residue was purified by chromatography with MeOH/NH.sub.3 (500:1).
The non-polar diastereomer (brown oil, 379 mg) was dissolved in
2-butanone (10 ml) and converted into the corresponding
dihydrochloride by the addition of chlorotrimethylsilane (319
.mu.l) (white solid; 405 mg; m.p. 234.degree.-236.degree. C.).
Example 83
[0470]
N,N-dimethyl-N'-[2-(5-methyl-1H-indol-3-yl)-ethyl]-1-phenylcyclohex-
ane-1,4-diamine dihydrochloride, polar diastereomer
[0471] As described for Example 82, the polar diastereomer (266 mg)
was also obtained, dissolved in 2-butanone (10 ml) and converted
into the corresponding dihydrochloride with ME.sub.3SiCl (224
.mu.l, 1.76 mmole) (white solid; 272 mg; m.p.
248.degree.-250.degree. C.).
Example 84
[0472]
Dimethyl-[1-phenyl-4-(1,3,4,9-tetrahydro-b-carbolin-2-yl)-cyclohexy-
l]-amine dihydrochloride
[0473] 2,3,4,9-tetrahydro-1H-.beta.-carboline (345 mg) and
4-dimethylamino-4-phenylcyclohexanone (435 mg) were dissolved in a
mixture of THF (10 ml) and 1,2-dichloroethane (15 ml) under argon,
followed by the addition of glacial acetic acid (120 mg, 2 mmole).
After 15 minutes NaBH(OAc).sub.3 (600 mg) was added, the reaction
mixture was stirred for 68 hours and concentrated by evaporation,
and the residue was taken up in 1 N hydrochloric acid (20 ml) and
washed with ether (2.times.20 ml). The aqueous solution was
adjusted alkaline with 1 M NaOH (30 ml) and extracted with ether
(3.times.30 ml). After drying and concentrating by evaporation the
combined extracts a semi-solid crude product was obtained, which
after column chromatography separation with methanol/NH.sub.3
(500:3) yielded the non-polar diastereomer (334 mg, m.p.
147.degree.-150.degree. C.), which was dissolved by heating in
2-butanone (20 ml) and ethanol (10 ml) and converted into the
corresponding dihydrochloride with 3.3 M ethanolic hydrochloric
acid (0.8 ml) (335 mg; m.p. 264.degree.-269.degree. C.)
Example 85
[0474]
N-(4-dimethylamino-4-phenylcyclohexyl)-N-[2-(4-fluorophenyl)-ethyl]-
-acetamide hydrochloride, non-polar diastereomer
[0475] 4-(fluorophenyl)ethylamine (1.15 g) and
4-dimethylamino-4-phenylcyc- lohexanone (1.8 g) were dissolved in
dry 1,2-dichloroethane (20 ml) and tetrahydrofuran (60 ml) with the
exclusion of oxygen. Glacial acetic acid (8.28 mmole) and sodium
triacetoxy boron hydride (2.48 g, 11.59 mmole) were added to this
mixture and stirred for 24 hours at RT. For working-up the reaction
mixture was concentrated by evaporation followed by the addition of
1 M HCl (20 ml) and diethyl ether (40 ml), the phases were
separated, and the aqueous phase was extracted with diethyl ether
(2.times.20 ml) and adjusted to pH 11 with 5 N NaOH. The aqueous
phase was diluted with water (10 ml) and extracted with ethyl
acetate (3.times.20 ml). The combined organic extracts were dried
over sodium sulfate, concentrated by evaporation, and the residue
was purified by chromatography on silica gel with methanol. The
non-polar diastereomer (531 mg, 1.55 mmole) was dissolved in
anhydrous pyridine (10 ml) and acetic anhydride (1.59 g, 15.59
mmole) was added while stirring. After 24 hours some ice cubes were
added to the reaction mixture and the latter was concentrated as
far as possible on a rotary evaporator. 1 M NaOH (20 ml) was added
to the residue. The aqueous phase was extracted with ethyl acetate
(3.times.30 ml) and the combined organic extracts were dried over
sodium sulfate and concentrated by evaporation. The acetamide
obtained (545 mg) was dissolved in 2-butanone (10 ml) and converted
into the corresponding hydrochloride with chlorotrimethylsilane
(0.270 ml) (white solid; 302 mg; m.p. 196.degree.-201.degree.
C.).
Example 86
[0476]
2-(4-dimethylamino-4-phenylcyclohexylamino)-3-(5-fluoro-1H-indol-3--
yl)-propionic acid methyl ester dihydrochloride, non-polar
diastereomer
[0477] 4-dimethylamino-4-phenylcyclohexanone (935 mg), sodium
sulfate (4 g) and glacial acetic acid (245 .mu.l, 4.4 mmole) were
added to rac-5-fluorotryptophan methyl ester (1030 mg) in
1,2-dichloroethane (ca. 40 ml) under argon. After stirring for 1
hour at RT sodium triacetoxy boron hydride was added (1.4 g, 6.5
mmole). The mixture was stirred for 3 days at RT. For working-up
the reaction mixture was concentrated by evaporation, the residue
was taken up in ethyl acetate (40 ml) and 1 M NaOH (35 ml), the
phases were separated and the aqueous phase was extracted three
times with ethyl acetate (10 ml each time). The combined extracts
were dried, concentrated by evaporation, and the residue obtained
(1.73 g) was purified by flash chromatography (eluent: MeOH/EtOAc
1:3). The non-polar diastereomer obtained (911 mg, m.p.
55.degree.-62.degree. C.) was dissolved in 2-butanone/acetone (7
ml/1 ml) and converted into the corresponding dihydrochloride with
chlorotrimethylsilane (174 .mu.l) (beige solid; 135 mg; m.p.
172.degree.-182.degree. C.).
Example 87
[0478]
N-(4-dimethylamino-4-phenylcyclohexyl)-N-(3-phenylpropyl)-acetamide
hydrochloride, non-polar diastereomer
[0479] 3-phenylpropylamine (676 mg) and
4-dimethylamino-4-phenylcyclohexan- one (1.086 g) were dissolved in
dry 1,2-dichloroethane (5 ml) and tetrahydrofuran (15 ml) with the
exclusion of oxygen. Glacial acetic acid (5 mmole) and sodium
triacetoxy boron hydride (1.5 g, 7 mmole) were added to this
mixture and stirred for 24 hours at RT. For working-up the mixture
was concentrated by evaporation, followed by the addition of 1 M
HCl (20 ml) and diethyl ether (40 ml). The aqueous phase was washed
with diethyl ether (2.times.20 ml), separated, adjusted to pH 11
with 5 N NaOH, diluted with water (10 ml) and extracted with ethyl
acetate (3.times.20 ml). The combined organic extracts were dried
over sodium sulfate and concentrated by evaporation. The crude
product obtained was purified by chromatography on silica gel with
methanol. 761 g of the non-polar diastereomer were obtained. 453 mg
were dissolved in anhydrous pyridine (10 ml) and acetic anhydride
(1.374 g) was added while stirring. After stirring for 24 hours at
RT some ice cubes were added and the mixture was concentrated as
far as possible on a rotary evaporator. 1 N NaOH (20 ml) was added
to the residue and the latter was extracted with ethyl acetate
(3.times.30 ml). The combined organic extracts were dried over
sodium sulfate and concentrated by evaporation. The acetamide
obtained (528 mg) was dissolved in 2-butanone (10 ml) and converted
into the corresponding hydrochloride with chlorotrimethylsilane
(0.353 ml) (white solid; 282 mg; m.p. 206.degree.-211.degree.
C.).
Example 88
[0480]
2-(4-dimethylamino-4-phenylcyclohexylamino)-3-(6-fluoro-1H-indol-3--
yl)-propionic acid methyl ester dihydrochloride, non-polar
diastereomer
[0481] 4-dimethylamino-4-phenylcyclohexanone (877 mg), sodium
sulfate (2 g) and glacial acetic acid (230 .mu.l, 4 mmole) were
added under argon to rac-6-fluorotryptophan methyl ester (952 mg)
in 1,2-dichloroethane (ca. 30 ml). After stirring for 1 hour at RT
sodium triacetoxy boron hydride (1.33 g, 6 mmole) was added and
stirred for 2 days at RT. For working-up the mixture was
concentrated by evaporation, the residue was dissolved in ethyl
acetate (30 ml) and 1 M NaOH (25 ml), the clear phases were
separated in a separating funnel, the aqueous phase was extracted
three times with ethyl acetate (10 ml each time) and the combined
extracts were dried and concentrated by evaporation. The residue
obtained (1.72 g) was purified by flash chromatography (eluent:
MeOH/EtOAc 1:2, followed by MeOH/EtOAc 1:1 and MeOH/NH.sub.3
400:1). The non-polar diastereomer (868 mg) was partially dissolved
(261 mg) in 2-butanone (7 ml) and the corresponding dihydrochloride
was precipitated with chlorotrimethylsilane (227 .mu.l) (white
solid; 224 mg; m.p. 164.degree.-169.degree. C.).
Example 89
[0482]
N-(4-dimethylamino-4-phenylcyclohexyl)-2-(1H-indol-3-yl)-acetamide
hydrochloride, polar diastereomer
[0483] 4-dimethylamino-4-phenylcyclohexanone (10 mg) and
hydroxylamine hydrochloride (4.8 g) were dissolved in absolute
ethanol (120 ml), Amberlyst A 21 basic ion exchanger (30.7 g) was
added to the solution and the mixture was stirred overnight at RT.
The ion exchanger was filtered off and washed with ethanol
(3.times.50 ml) on the frit. The ethanol was removed in vacuo, the
residue was adjusted to pH 11 with 5 M NaOH, diluted with water,
and extracted with ethyl acetate (4.times.30 ml). The combined
extracts were dried over sodium sulfate and concentrated by
evaporation. 11 g of 4-dimethylamino-4-phenylcyclohexanone oxime
were obtained. 4-dimethylamino-4-phenylcyclohexanone oxime (11 mg)
was dissolved in methanol (200 ml) and diluted with 5 M NaOH (200
ml). Devarda's alloy (30 g) was added in portions to this mixture.
The reaction temperature was between 500 and 60.degree. C. 15
minutes after completion of the addition the mixture was diluted
with water (150 ml), the methanol was removed in vacuo and the
aqueous solution was extracted with ether (5.times.50 ml). The
combined extracts were dried over sodium sulfate and concentrated
by evaporation. N,N-dimethyl-1-phenylcyclohexane- -1,4-diamine was
obtained as a yellow oil (10.0 g).
[0484] N-methylmorpholine (235 .mu.l, 2.1 mmole) and
2-chloro-4,6-dimethoxyl-1,3,5-triazine (371 mg, 2.11 mmole) were
added to a solution of indol-3-ylacetic acid (257 mg) in absolute
THF (10 ml). The mixture was then stirred for 1 hour at RT.
Following this the polar diastereomer of
N,N-dimethyl-1-phenylcyclohexane-1,4-diamine (320 mg) was added to
the mixture and stirred for 12 hours at RT. For working-up the
mixture was concentrated by evaporation, adjusted to pH 11 with 5 M
NaOH, the phases were separated and the aqueous phase was diluted
with water (10 ml) and extracted with ethyl acetate (3.times.20
ml). The combined organic extracts were dried over sodium sulfate
and concentrated by evaporation. The amide obtained was purified by
column chromatography with ethyl acetate/ethanol (1:1) and
dissolved (120 mg) in 2-butanone (3 ml) and converted into the
corresponding hydrochloride with chlorotrimethylsilane (61 .mu.l)
(white solid; 128 mg; m.p. 100.degree.-102.degree. C.).
Example 90
[0485]
2-(4-dimethylamino-4-thiophen-2-yl-cyclohexylamino)-3-(1H-indol-3-y-
l)-propionic acid methyl ester dihydrochloride, non-polar
diastereomer
[0486] The hydrochloride of L-tryptophan methyl ester (1.01 g) was
vigorously for 15 minutes with 1,2-dichloroethane (20 ml) and
saturated NaHCO.sub.3 solution (20 ml) and the aqueous phase was
immediately extracted with 1,2-dichloroethane (2.times.20 ml).
After drying over sodium sulfate the organic phase was concentrated
by evaporation to 40 ml and 4-dimethylamino-4-phenylcyclohexanone
(893 mg, 4 mmole) was added under argon. Glacial acetic acid (0.228
ml, 4 mmole) and sodium sulfate (2 g) were added to the clear
solution. After a reaction time of 15 minutes NaBH(OAc).sub.3 (1.2
g) was added to the reaction mixture and stirred for 4 days at room
temperature. For working-up saturated NaHCO.sub.3 solution (40 ml)
was added and stirred for 15 minutes. The aqueous phase was
extracted with dichloromethane (2.times.20 ml). The combined
organic phases were dried and then concentrated by evaporation, a
pale brown oil being obtained. Column chromatography purification
was carried out with ethyl acetate and methanol. The non-polar
diastereomer (918 mg; m.p. 108.degree.-112.degree. C.) was
dissolved in 2-butanone (15 ml) and converted into the
corresponding dihydrochloride with chlorotrimethylsilane (0.4 ml)
(white solid; 326 mg; m.p. 197.degree.-202.degree. C.).
Example 91
[0487]
N-(4-dimethylamino-4-phenylcyclohexyl)-2-(5-methoxy-1H-indol-3-yl)--
acetamide hydrochloride, non-polar diastereomer
[0488] The non-polar diastereomer of
N,N-dimethyl-1-phenylcyclohexane-1,4-- diamine (387 mg) and
4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholi- nium
chloride (267 mg, 2.0 mmole) were added to a solution of
(5-methoxy-1H-indol-3-yl)-acetic acid (364 mg) in absolute methanol
(20 ml). The mixture was then stirred for 24 hours at RT. For
working-up the mixture was concentrated by evaporation, diluted
with water (10 ml), adjusted to pH 11 with 5 M NaOH and extracted
with ethyl acetate (3.times.20 ml). The combined organic extracts
were dried over sodium sulfate and concentrated by evaporation.
After column chromatography with MeOH the non-polar amide (154 mg;
colourless oil) was dissolved in 2-butanone (5 ml) and converted
into the corresponding hydrochloride with chlorotrimethylsilane (72
.mu.l) (white solid; 168 mg; m.p. 143.degree.-145.degree. C.).
Example 92
[0489]
N,N-dimethyl-1-phenyl-N'-(2-pyridin-4-yl-ethyl)-cyclohexane-1,4-dia-
mine trihydrochloride
[0490] 2-(pyridin-4-yl)ethylamine (484 mg) and
4-dimethylamino-4-phenylcyc- lohexanone (434 mg) were dissolved in
dry 1,2-dichloroethane (10 ml) under the exclusion of oxygen.
Glacial acetic acid (2 mmole) and sodium triacetoxy boron hydride
(600 mg) were added to this mixture and stirred for 24 hours at RT.
For working-up the mixture was concentrated by evaporation and
adjusted to pH 11 with 5 M NaOH. The alkaline phase was diluted
with water (10 ml) and extracted with ethyl acetate (3.times.20
ml). The combined organic phases were dried over sodium sulfate,
concentrated by evaporation and purified by chromatography with
MeOH. The crude product obtained (420 mg) was dissolved in
2-butanone (10 ml) and converted into the trihydrochloride with
chlorotrimethylsilane (577 .mu.l) (white solid; 560 mg; m.p.
143.degree.-148.degree. C.). This compound also exhibited inter
alia an affinity for the ORL1 receptor, expressed as a K.sub.i
value in .mu.m of 0.23.
Example 93
[0491]
N,N-dimethyl-1-phenyl-N'-(2-pyridin-2-yl-ethyl)-cyclohexane-1,4-dia-
mine dihydrochloride, non-polar diastereomer
[0492] 2-(pyridin-2-yl)ethylamine (363 mg) and
4-dimethylamino-4-phenylcyc- lohexanone (434 mg) were dissolved in
dry 1,2-dichloroethane (10 ml) under the exclusion of oxygen.
Glacial acetic acid (2 mmole) and sodium triacetoxy boron hydride
(600 mg) were added to this mixture. The mixture was then stirred
for 24 hours at RT. For working-up the mixture was concentrated by
evaporation and the residue was adjusted to pH 11 with 5 M NaOH,
diluted with water (10 ml) and extracted with ethyl acetate
(4.times.20 ml). The combined organic extracts were dried over
sodium sulfate and concentrated by evaporation. The crude product
was purified by chromatography with MeOH. The non-polar
diastereomer was obtained as a colourless oil in a yield of 210 mg
(33%), dissolved in 2-butanone (5 ml) and converted into the
corresponding dihydrochloride with chlorotrimethylsilane (288
.mu.l) (white solid; 285 mg; m.p. 115.degree.-118.degree. C.). This
compound also exhibited inter alia an affinity for the ORL1
receptor, expressed as a K.sub.i value in .mu.m of 0.089. In the
tail flick test in mice the substance was 100% (1) active as
measured by the antinociceptive action compared to the control
group according to Example 106.
Example 94
[0493] Potassium
(S)-2-(4-dimethylamino-4-phenylcyclohexylamino)-3-(1H-ind-
ol-3-yl)-propionate, non-polar diastereomer
[0494] 200 ml of methanol, 1680 ml of aqueous dimethylamine
solution (40 m %), 303 g of dimethylamine hydrochloride and 200 g
of potassium cyanide were added to 200 g of
1,4-dioxaspiro[4.5]-decan-8-one and stirred for ca. 65 hours. The
white suspension obtained was extracted four times with 800 ml of
ether each time, the combined extracts were concentrated by
evaporation, and the residue was taken up in ca. 500 ml of
dichloromethane and the phases were separated. The organic phase
was dried over sodium sulfate, filtered and concentrated by
evaporation. 265 g of
8-dimethylamino-1,4-dioxaspiro[4.5]-decane-8-carbonitrile were
obtained as a white solid.
[0495] 50.0 g of
8-dimethylamino-1,4-dioxaspiro[4.5]-decane-8-carbonitrile were
dissolved in 400 ml of tetrahydrofuran of analysis purity, 216 ml
of a commercially obtainable 2 M solution of phenyl magnesium
chloride in tetrahydrofuran were added dropwise under a nitrogen
atmosphere while cooling in an ice bath, and the whole was stirred
overnight while heating to room temperature. For working-up 200 ml
of ice-cold ammonium chloride solution (20 m %) were added while
stirring and cooling in an ice bath, and after 30 minutes the
phases were separated. The aqueous phase was extracted twice with
250 ml of ether each time, the extracts were combined with the
organic phase, washed with 200 ml of water followed by 200 ml of
saturated sodium chloride solution, dried over sodium sulfate,
filtered and concentrated by evaporation. 60.0 g of
dimethyl-(8-phenyl-1,4-dioxaspiro[4.5]dec-8-yl)amine were
obtained.
[0496] 165 ml of hydrochloric acid (32 m %) were diluted with 100
ml of water, followed by the addition of ca. 6 M hydrochloric acid
and 60.0 g of
dimethyl-(8-phenyl-1,4-dioxaspiro[4.5]-dec-8-yl)amine, and the
whole was stirred for 24 hours. The reaction mixture was washed
three times with 50 ml of diethyl ether each time, adjusted
alkaline (pH>10) with 100 ml of sodium hydroxide (32 m %), and
extracted three times with 100 ml of dichloromethane each time. The
extracts were combined, dried over sodium sulfate, filtered and
concentrated by evaporation. 36.1 g of
4-dimethylamino-4-phenylcyclohexanone were obtained.
[0497] In order to release the base, L-tryptophan methyl ester
hydrochloride (509 mg) was suspended in 1,2-dichloroethane (10 ml)
and vigorously stirred for 2 minutes with concentrated aqueous
ammonia solution (10 ml). The phases were separated and the aqueous
phase was extracted with 1,2-dichloroethane (2.times.10 ml). The
combined extracts were dried over sodium sulfate and concentrated
to about 20 ml by evaporation on a rotary evaporator.
4-dimethylamino-4-phenylcyclohexanone (435 mg), glacial acetic acid
(57 .mu.l) and fused sodium sulfate (2 g) were added to the
previously prepared dried solution of tryptophan methyl ester (438
mg) in 1,2-dichloroethane (ca. 20 ml). After stirring for 2 hours
at RT sodium triacetoxy boron hydride (660 mg) was added and
stirring was continued. After 3 days the solvent was removed in
vacuo and the residue was suspended in diethyl ether (20 ml) and 1
M NaOH (5 ml). After the extraction of the aqueous phase with ether
and ethyl acetate (each 3.times.10 ml) the combined organic
extracts were washed twice with 1 M NaOH (5 ml), then dried and
concentrated by evaporation. The viscous residue (718 mg) was
purified twice by flash chromatography (silica gel; eluent:
EtOAc/MeOH (3:1) as well as EtOAc/MeOH (1:1)). The non-polar
diastereomer (385 mg) was dissolved in ethanol, 1.7 M potassium
hydroxide solution (10.8 ml) was added to the clear solution, and
the mixture was stirred for 20 hours at RT. For working-up the
ethanol was distilled off, water (20 ml) and ethyl acetate (30 ml)
were added to the oily residue, and the mixture was stirred
vigorously for 1 hour at RT. During this time the potassium salt
formed as a white precipitate between the phases. The solid was
suction filtered, washed with water (1.times.3 ml) and EtOAc
(3.times.5 ml) and then dried. The non-polar diastereomer of
potassium
(S)-2-(4-dimethylamino-4-phenylcyclohexylamino)-3-(1H-indol-3-yl)-propion-
ate was thus obtained as a white solid (309 mg; m.p.
190.degree.-196.degree. C.).
Example 95
[0498] Potassium
rac-2-(4-dimethylamino-4-phenylcyclohexylamino)-3-(5-fluo-
ro-1H-indol-3-yl)-propionate, non-polar diastereomer
[0499] rac-5-fluorotryptophan methyl ester hydrochloride (1.12 g)
was suspended in 1,2-dichloroethane (30 ml) and stirred vigorously
for 5 minutes with concentrated aqueous ammonia solution (30 ml).
The phases were then separated in a separating funnel. The aqueous
solution was extracted twice with 1,2-dichloroethane (15 ml each
time). The combined extracts were dried over sodium sulfate, the
solvent volume was reduced to about 40 ml on a rotary evaporator,
and the solution of rac-5-fluorotryptophan methyl ester that was
obtained was used for the reductive amination described
hereinafter. 4-dimethylamino-4-phenylcycloh- exanone (935 mg),
sodium sulfate (4 g) and glacial acetic acid (245 .mu.l) were added
under argon to the solution of rac-5-fluorotryptophan methyl ester
(1030 mg) in 1,2-dichloroethane (ca. 40 ml). After stirring for 1
hour at RT sodium triacetoxy boron hydride (1.4 g) was added and
the mixture was stirred for 3 days at RT. For working-up the
solvent was removed in vacuo and the residue was dissolved in ethyl
acetate (40 ml) and 1 M NaOH (35 ml). The clear phases were
separated in a separating funnel and the aqueous phase was washed
three times with EtOAc (10 ml each time). The combined EtOAc phases
were then dried and concentrated by evaporation. The crude product
obtained (1.73 g) was separated by flash chromatography (silica gel
60, eluent: 1000 ml MeOH/EtOAc (1:3), 800 ml MeOH/EtOAc (1:1) and
1000 ml MeOH). The non-polar diastereomer (911 mg, m.p.
55.degree.-62.degree. C.) was separated and 673 mg thereof were
dissolved in ethanol (60 ml). 1.7 N potassium hydroxide solution
(18.1 ml) was added to the clear solution. After stirring for 20
hours at RT the ethanol was distilled off. Water (20 ml) and EtOAc
(50 ml) were added to the oily residue and stirred for 1 hour at
RT. During this time potassium
2-(4-dimethylamino-4-phenylcyclohexylamino)-3-(5-fluoro-1H-indo-
l-3-yl)-propionate formed as a white precipitate between the
phases. The solid was suction filtered, washed with EtOAc
(3.times.5 ml) and dried (white solid; 641 mg; m.p.
175.degree.-180.degree. C.).
Example 96
[0500] Potassium
rac-2-(4-dimethylamino-4-phenylcyclohexylamino)-3-(6-fluo-
ro-1H-indol-3-yl)-propionate, non-polar diastereomer
[0501] rac-6-fluorotryptophan methyl ester hydrochloride (1.1 g)
was suspended in 1,2-dichloroethane (30 ml) and stirred vigorously
for 5 minutes with concentrated aqueous ammonia solution (20 ml).
The phases were then separated in a separating funnel. The aqueous
solution was extracted twice with 1,2-dichloroethane (15 ml each
time). The combined extracts were dried over sodium sulfate and the
solvent volume was reduced to about 30 ml on a rotary evaporator.
The solution of the rac-6-fluorotryptophan methyl ester obtained
was used for the reductive amination.
[0502] 4-dimethylamino-4-phenylcyclohexanone (877 mg), sodium
sulfate (2 g) and glacial acetic acid (230 .mu.l) were added under
argon to the solution of rac-6-fluorotryptophan methyl ester (952
mg) in 1,2-dichloroethane (ca. 30 ml). After stirring for 1 hour at
RT sodium triacetoxy boron hydride (1.33 g) was added and the
mixture was stirred for 2 days at RT. For working-up the solvent
was removed in vacuo and the residue was dissolved in ethyl acetate
(30 ml) and 1 M NaOH (25 ml). The clear phases were separated in a
separating funnel and the aqueous phase was washed three times with
EtOAc (10 ml each time). The combined EtOAc phases were dried and
concentrated by evaporation. The residue (1.72 g) was separated by
flash chromatography (150 g silica gel 60, eluent: 1000 ml
MeOH/EtOAc (1:2), 600 ml MeOH/EtOAc (1:1) and 1500 ml MeOH/NH.sub.3
(400:1). The non-polar diastereomer (868 mg) was separated cleanly
and 613 mg thereof were dissolved in ethanol (60 ml). 1.7 N
potassium hydroxide solution (16.5 ml) was added to the clear
solution. After stirring for 20 hours at RT the ethanol was
distilled off, water (20 ml) and EtOAc (70 ml) were added to the
oily residue, and the whole was vigorously stirred for 2 days at
RT. During this time potassium
2-(4-dimethylamino-4-phenylcyclohexylamino)-3-(6-fluoro-1H-indol-3-yl)-pr-
opionate separated out as a white precipitate between the phases.
The solid was suction filtered, washed with EtOAc (3.times.5 ml)
and dried (570 mg; m.p. 207.degree.-212.degree. C.).
Example 97
[0503] Potassium
(S)-2-(4-dimethylamino-4-thiophen-2-yl-cyclohexylamino)-3-
-(1H-indol-3-yl)-propionate, non-polar diastereomer
[0504] 2-iodothiophene (22.9 g) were dissolved in THF (80 ml) under
argon and 2 M isopropyl magnesium chloride (35.7 ml) in THF was
added within 30 minutes at 0.degree. C. After a reaction time of 1
hour at 3.degree.-5.degree. C.,
8-dimethylamino-1,4-dioxaspiro[4.5]decane-8-carbo- nitrile (10 g)
dissolved in tetrahydrofuran (20 ml) was added and stirred for 20
hours at room temperature. For working-up saturated NH.sub.4Cl
solution was added (85 ml), the product was extracted with diethyl
ether (3.times.100 ml) and the combined extracts were washed with
water (50 ml) and saturated NaCl solution (50 ml), dried and
concentrated by evaporation. The crude product obtained (21.3 g of
dark brown oil) was dissolved in 2-butanone (140 ml) and converted
with chlorotrimethylsilane (9.1 ml) into the hydrochloride of
dimethyl-(8-thiophen-2-yl-1,4-dioxaspi- ro[4.5]dec-8-yl)-amine
(white solid; 8.74 g).
[0505] Dimethyl-(8-thiophen-2-yl-1,4-dioxaspiro[4.5]dec-8-yl)-amine
hydrochloride (8.68 g) was dissolved in 7.5 M hydrochloric acid (29
ml), stirred for 48 hours at room temperature and then extracted
with diethyl ether (2.times.50 ml). The aqueous phase was adjusted
alkaline with 5 M sodium hydroxide while cooling with ice,
extracted with dichloromethane (3.times.50 ml), dried and
concentrated by evaporation.
4-dimethylamino-4-thiophen-2-yl-cyclohexanone was thus obtained as
a yellow solid (5.66 g; m.p. 108.degree.-110.degree. C.).
[0506] The hydrochloride of L-tryptophan methyl ester (1.01 g) was
vigorously stirred for 15 minutes with 1,2-dichloroethane (20 ml)
and saturated NaHCO.sub.3 solution (20 ml) and the aqueous phase
was immediately extracted with 1,2-dichloroethane (2.times.20 ml).
After drying over sodium sulfate the organic phase was concentrated
by evaporation to 40 ml and
4-dimethylamino-4-thiophen-2-yl-cyclohexanone (893 mg) was added
under argon. Glacial acetic acid (0.228 ml) and sodium sulfate (2
g) were added to the clear solution. After a reaction time of 15
minutes NaBH(OAc).sub.3 (1.2 g) was added to the reaction mixture
and stirred for 4 days at room temperature. For working-up
saturated NaHCO.sub.3 solution (40 ml) was added to the mixture and
stirred for 15 minutes. The aqueous phase was extracted with
dichloromethane (2.times.20 ml). The combined organic extracts were
dried and concentrated by evaporation, a pale brown oil being
obtained. Column chromatography separation of the crude product was
carried out with ethyl acetate and methanol. 500 mg of the
non-polar diastereomer obtained (918 mg; m.p.
108.degree.-112.degree. C.) were dissolved in ethanol (50 ml).
After the addition of 1.7 N KOH (13.8 ml, 23.5 mmole) a slight
turbidity occurred, which disappeared during the hydrolysis. After
a reaction time of 2.5 days the mixture was concentrated by
evaporation, an oil separating out that was soluble in water (30
ml). After the addition of ethyl acetate (20 ml) the mixture was
stirred for 30 minutes, potassium
(S)-2-(4-dimethylamino-4-thiophen-2-yl-cyclohexylamino)-3-(1H-indol-3-yl)-
-propionate precipitating out as a white solid (291 mg).
Example 98
[0507]
(S)-2-(4-dimethylamino-4-thiophen-2-yl-cyclohexylamino)-3-(1H-indol-
-3-yl)-propionic acid hydrochloride, polar diastereomer
[0508] As described for Example 97, 432 mg of the polar
diastereomer of
2-(4-dimethylamino-4-thiophen-2-yl-cyclohexylamino)-3-(1H-indol-3-yl)-pro-
pionic acid methyl ester were also obtained (m.p.
55.degree.-58.degree. C.). 250 mg were dissolved in ethanol (20 ml)
and 1.7 M KOH (6.9 ml). After 2.5 days the mixture was concentrated
by evaporation and the remaining yellow oil was dissolved in water
(20 ml), washed with ethyl acetate (2.times.20 ml) followed by the
addition of 5.5 N HCl (2.72 ml). Since no hydrochloride had
precipitated the aqueous phase was concentrated by evaporation and
stirred with ethanol (2.times.30 ml). The remaining KCl was
separated off and the filtrate was concentrated by evaporation. In
this way, after treatment with ether,
(S)-2-(4-dimethylamino-4-thiophen-2-yl-cyclohexylamino)-3-(1H-indol-3-yl)-
-propionic acid hydrochloride was obtained as a beige-coloured
solid (223 mg, m.p. 196.degree.-199.degree. C.)
Example 99
[0509]
(S)-2-(4-dimethylamino-4-thiophen-2-yl-cyclohexylamino)-3-(1H-indol-
-3-yl)-propionic acid hydrochloride, polar diastereomer
[0510] The hydrochloride of L-phenylalanine methyl ester (1.29 g)
was vigorously stirred for 15 minutes with 1,2-dichloroethane (40
ml) and saturated NaHCO.sub.3 solution (40 ml) and the aqueous
phase was immediately extracted with 1,2-dichloroethane (2.times.40
ml). After drying over sodium sulfate the organic phase was
concentrated to 40 ml by evaporation and
4-dimethylamino-4-phenylcyclohexanone (1.3 g) was added under
argon. Glacial acetic acid (0.345 ml) and sodium sulfate (3 g) were
added to the clear solution. After a reaction time of 15 minutes
NaBH(OAc).sub.3 (1.8 g) was added to the reaction mixture and
stirred for 2 days at room temperature. For working-up saturated
NaHCO.sub.3 solution (60 ml) was added to the mixture and stirred
for 15 minutes. The aqueous phase was extracted with
dichloromethane (2.times.40 ml). The combined organic extracts were
dried and then concentrated by evaporation, a pale brown oil being
obtained. Chromatographic separation of the substance mixture on
silica gel was carried out with ethyl acetate/methanol (20:1). The
non-polar product (1.29 g) was obtained as a beige-coloured
compound. 400 mg of this compound were dissolved in ethanol (30 ml)
and 1.7 M KOH (12.4 ml). After 1 day the reaction mixture was
concentrated by evaporation, an oil separating out that redissolved
in water (20 ml). The aqueous solution was washed with ethyl
acetate (2.times.20 ml) and 5.5 N HCl (4.77 ml) was added. Since no
hydrochloride had precipitated, the aqueous phase was concentrated
by evaporation and the residue was stirred with ethanol (2.times.20
ml). The remaining KCl was separated and the filtrate was
concentrated by evaporation. (S)-2-(4-dimethylamino-4-thioph-
en-2-yl-cyclohexylamino)-3-(1H-indol-3-yl)-propionic acid
hydrochloride was obtained in this way (436 mg, m.p.
205.degree.-207.degree. C.).
Example 100
[0511] Potassium
rac-2-(4-dimethylamino-4-phenylcyclohexylamino)-4-phenylb- utyrate,
non-polar diastereomer
[0512] The hydrochloride of 2-amino-4-phenylbutyric acid methyl
ester (1.37 g) was vigorously stirred for 15 minutes with
1,2-dichloroethane (30 ml) and saturated NaHCO.sub.3 solution (30
ml) and the aqueous phase was immediately extracted with
1,2-dichloroethane (2.times.30 ml). After drying over sodium
sulfate the organic phase was concentrated to 40 ml by evaporation
and 4-dimethylamino-4-phenylcyclohexanone (1.3 g) was added under
argon. Glacial acetic acid (0.345 ml) and sodium sulfate (3 g) were
added to the clear solution. After a reaction time of 15 minutes
NaBH(OAc).sub.3 (1.8 g) was added to the reaction mixture and
stirred for 4 days at room temperature. For working-up saturated
NaHCO.sub.3 solution (60 ml) was added to the mixture and stirred
for 15 minutes. The aqueous phase was extracted with
dichloromethane (2.times.30 ml). The combined organic extracts were
dried and then concentrated by evaporation, an oil being obtained.
Chromatographic separation of the substance mixture on silica gel
was carried out with ethyl acetate/methanol (20:1). The non-polar
product (1.34 g) was obtained as a beige-coloured compound, 484 mg
of which were dissolved in ethanol (25 ml) and 1.7 M KOH (14.4 ml).
After a reaction time of 3 days the mixture was concentrated by
evaporation, an oil separating out that redissolved in water (20
ml). After the addition of ethyl acetate (20 ml), potassium
2-(4-dimethylamino-4-phenylcyclohexylamino)-4-phenylbutyrate
crystallised out as a white solid (427 mg; m.p.
207.degree.-210.degree. C.).
Example 101
[0513]
rac-2-(4-dimethylamino-4-phenylcyclohexylamino)-4-phenylbutyric
acid hydrochloride, polar diastereomer
[0514] As described for Example 100, 733 mg of the polar
diastereomer of
rac-2-(4-dimethylamino-4-phenylcyclohexylamino)-4-phenylbutyric
acid methyl ester were also obtained.
[0515] 225 mg were dissolved in ethanol (20 ml) and 1.7 M KOH (6.7
ml). After 3 days the mixture was concentrated by evaporation, the
remaining oil was dissolved in water (20 ml), washed with ethyl
acetate (2.times.20 ml) and 5.5 N HCl (2.6 ml) was added. Since no
hydrochloride had precipitated out the aqueous phase was
concentrated by evaporation and stirred with ethanol (2.times.30
ml). The remaining KCl was separated off and the filtrate was
concentrated by evaporation. The polar diastereomer of
rac-2-(4-dimethylamino-4-phenylcyclohexylamino)-4-phenylbutyric
acid hydrochloride was thus obtained (240 mg, m.p.
153.degree.-155.degree. C.).
Example 102
[0516]
(R)-2-(4-dimethylamino-4-phenylcyclohexylamino)-3-(1H-indol-3-yl)-p-
ropionic acid hydrochloride, non-polar diastereomer
[0517] The hydrochloride of D-tryptophan methyl ester (1.49 g) was
vigorously stirred for 15 minutes with 1,2-dichloroethane (40 ml)
and saturated NaHCO.sub.3 solution (40 ml) and the aqueous phase
was immediately extracted with 1,2-dichloroethane (2.times.40 ml).
After drying over sodium sulfate the organic phase was concentrated
to 40 ml by evaporation and 4-dimethylamino-4-phenylcyclohexanone
(1.48 g) was added under argon. Glacial acetic acid (0.392 ml) and
sodium sulfate (3.4 g) were added to the clear solution. After a
reaction time of 15 minutes NaBH(OAc).sub.3 (2.05 g) was added to
the reaction mixture and stirred for 2 days at room temperature.
For working-up saturated NaHCO.sub.3 solution (60 ml) was added to
the mixture and stirred for 15 minutes. The aqueous phase was
extracted with dichloromethane (2.times.40 ml). The combined
organic phases were dried and then concentrated by evaporation, a
pale brown oil being obtained. Chromatographic separation of the
substance mixture on silica gel was carried out with ethyl
acetate/methanol (1.5:1). The non-polar product (1.64 g) was
obtained as a beige-coloured compound, 640 mg of which were
dissolved in ethanol (30 ml) and 1.7 N KOH (17.8 ml). After a
reaction time of 2 days the mixture was concentrated by
evaporation, an oil separating out that remained undissolved in
water (20 ml) and ethyl acetate (20 ml). 5.5 N HCl (6.9 ml) was
added to the aqueous phase with the oil. Since no hydrochloride
precipitated out, the aqueous phase was concentrated by evaporation
and the residue was digested with ethanol (2.times.20 ml). The
remaining KCl was separated and the filtrate was concentrated by
evaporation. The hydrochloride of the non-polar diastereomer of
(R)-2-(4-dimethylamino-4-p-
henylcyclohexylamino)-3-(1H-indol-3-yl)-propionic acid was thereby
obtained (383 mg, m.p. 181.degree.-195.degree. C.).
Example 103
[0518]
(R)-2-(4-dimethylamino-4-phenylcyclohexyl-amino)-3-phenylpropionic
acid hydrochloride, non-polar diastereomer
[0519] The hydrochloride of D-phenylalanine methyl ester (1.29 g)
was vigorously stirred for 20 minutes with 1,2-dichloroethane (30
ml) and saturated NaHCO.sub.3 solution (30 ml) and the aqueous
phase was immediately extracted with 1,2-dichloroethane (2.times.30
ml). The residue (960 mg) obtained after drying with sodium sulfate
and concentration by evaporation was dissolved in
1,2-dichloroethane (50 ml) and
4-dimethylamino-4-phenylcyclohexanone (1.16 g) was added under
argon. Glacial acetic acid (0.295 ml) and sodium sulfate (2 g) were
added to the clear solution. After a reaction time of 15 minutes
NaBH(OAc).sub.3 (1.6 g) was added to the reaction mixture and
stirred for 2 days at room temperature. Saturated NaHCO.sub.3
solution (60 ml) was added to the mixture and stirred for 15
minutes. The aqueous phase was extracted with dichloromethane
(2.times.40 ml). The combined organic phases were then dried and
concentrated by evaporation, a pale brown oil being obtained.
Chromatographic separation of the substance mixture on silica gel
was carried out with ethyl acetate/cyclohexane (2:1). 300 mg of the
pale yellow non-polar product (1.16 g;
[.alpha.].sup.20.sub.D=-2.79, (c=1.33 in trichloromethane)) were
dissolved in ethanol (30 ml) and 1.7 N KOH (9.3 ml). After 2 days
at room temperature the mixture was concentrated by evaporation. An
oil then separated out which dissolved in water (20 ml). The
aqueous phase was washed with ethyl acetate (2.times.20 ml) and 5.5
N HCl (3.6 ml, 20 mmole) was added. Since no hydrochloride had
precipitated out, the aqueous phase was concentrated by evaporation
and the residue was digested with ethanol (2.times.20 ml). The
remaining KCl was filtered off and the filtrate was concentrated by
evaporation. The hydrochloride of the non-polar acid of
(R)-2-(4-dimethyl-amino-4-phenylcy-
clohexylamino)-3-phenylpropionic acid was thus obtained (230 mg,
m.p. 211.degree.-217.degree. C.).
Example 104
[0520]
rac-2-(4-dimethylamino-4-phenylcyclohexyl-amino)-3-(3-hydroxyphenyl-
)-propionic acid hydrochloride
[0521] The hydrochloride of 2-amino-3-(3-hydroxyphenyl) propionic
acid methyl ester (1.16 g) was stirred for 10 minutes with
saturated NaHCO.sub.3 solution (30 ml). The solution was then
evaporated to dryness on a rotary evaporator. The solid white
residue was vigorously stirred with ethanol (2.times.50 ml), each
time for 10 minutes, suction filtered, and the combined filtrates
were concentrated by evaporation. The 2-amino-3-(3-hydroxyphenyl)
propionic acid methyl ester obtained was dissolved in
1,2-dichloroethane (50 ml) under argon and
4-dimethylamino-4-phenylcyclohexanone (869 mg) was added. Glacial
acetic acid (0.23 ml) and sodium sulfate (2 g) were added to the
clear solution. After a reaction time of 15 minutes NaBH(OAc).sub.3
(1.2 g) was added to the reaction mixture and stirred for 2 days at
room temperature. For working-up saturated NaHCO.sub.3 solution (40
ml) was added to the mixture and stirred for 15 minutes. The
aqueous phase was extracted with dichloromethane (2.times.20 ml).
The combined organic phases were dried and then concentrated by
evaporation, an oil being obtained. Chromatographic separation of
the substance mixture on silica gel was carried out with ethyl
acetate/methanol (15:1) and carried out once more with
chloroform/methanol (20:1). 219 mg of the crude product obtained
(632 mg of a pale brown oil) were dissolved in ethanol (22 ml) and
1.7 N KOH (5.75 ml). After a reaction time of 44 hours the mixture
was concentrated by evaporation. An oil then separated out, which
dissolved in water (20 ml). The aqueous phase was washed with ethyl
acetate (2.times.20 ml) and 5.5 N HCl (2.12 ml) was added. Since no
hydrochloride precipitated out, the aqueous phase was concentrated
by evaporation and the residue was digested with ethanol
(2.times.20 ml). The remaining KCl was separated and the filtrate
was concentrated by evaporation. The hydrochloride of
rac-2-(4-dimethylamino-4-phenylcyclohexylamino)-3-(3-hyd-
roxyphenyl)-propionic acid were thus obtained (593 mg; m.p.
115.degree.-125.degree. C.).
Example 105
[0522]
N-(4-dimethylamino-4-pyridin-2-yl-cyclohexyl)-N-[2-(1H-indol-3-yl)--
ethyl]-acetamide dihydrochloride, non-polar diastereomer
[0523] 200 ml of methanol, 1680 ml of aqueous dimethylamine
solution (40 m %), 303 g of dimethylamine hydrochloride and 200 g
of potassium cyanide were added to 200 g of
1,4-dioxaspiro[4.5]decan-8-one and stirred for ca. 65 hours. The
white suspension obtained was extracted four times with 800 ml of
ether each time, the combined extracts were concentrated by
evaporation, the residue was taken up in ca. 500 ml of
dichloromethane and the phases were separated. The organic phase
was dried over sodium sulfate, filtered and concentrated by
evaporation. 265 g of
8-dimethylamino-1,4-dioxaspiro[4.5]decane-8-carbonitrile were
obtained as a white solid.
[0524] A solution of 4.5 g of
8-dimethylamino-1,4-dioxaspiro[4.5]-decane-8- -carbonitrile, 50 mg
of cyclopentadienyl-cycloocta-1,5-diene cobalt (I) [cpCo(cod)] and
100 ml of toluene was added to the reaction vessel in a
countercurrent of protective gas/acetylene. After saturation with
acetylene the reaction solution was irradiated 6 hours while
stirring vigorously at a temperature of 25.degree. C. The reaction
was interrupted by switching off the lamps and air feed and the
reaction solution was concentrated by evaporation. The crude
product obtained (5.47 g) was taken up in a mixture of water (8.7
ml) and concentrated hydrochloric acid (15 ml) and stirred
overnight at RT. For working-up the mixture was washed with diethyl
ether (3.times.100 ml), the phases were separated, the aqueous
phase was adjusted alkaline with 32 wt. % sodium hydroxide,
extracted with dichloromethane (3.times.100 ml), and the combined
extracts were dried (sodium sulfate), filtered and concentrated by
evaporation. 3.72 g of 4-dimethylamino-4-pyridin-2-yl-cyclohexanone
were obtained.
[0525] Acetic acid (0.448 ml) was added to a solution of
4-dimethylamino-4-pyridin-2-yl-cyclohexanone (873 mg) and
tryptamine (640 mg) in dry tetrahydrofuran (40 ml) and anhydrous
1,2-dichloroethane (10 ml) under argon and stirred for 15 minutes.
After the addition of sodium triacetoxy boron hydride (1.2 g) the
reaction mixture was stirred for 3 days under argon at room
temperature. For working-up the solvent was removed in vacuo, the
residue was taken up in 1 N sodium hydroxide (40 ml) and diethyl
ether (40 ml), the phases were separated, the aqueous phase was
extracted with diethyl ether (2.times.30 ml), and the organic
phases were combined, dried and concentrated by evaporation. The
crude product obtained was separated by column chromatography on
silica gel with methanol and methanol/ammonia (100:1). The
non-polar diastereomer of
N'-[2-(1H-indol-3-yl)-ethyl]-N,N-dimethyl-1-pyridin-2-yl-cyclohexane-1,4--
diamine was obtained as a white solid (617 mg; m.p.
150.degree.-152.degree. C.).
[0526]
N'-[2-(1H-indol-3-yl)-ethyl]-N,N-dimethyl-1-pyridin-2-yl-cyclohexan-
e-1,4-diamine (250 mg) was dissolved in dry pyridine (5 ml), acetic
anhydride (0.64 ml) was added and the mixture was stirred for 22
hours at room temperature. Some ice was added to the reaction
mixture, which was then concentrated by evaporation. The residue
was taken up in 1 M sodium hydroxide (20 ml) and ethyl acetate (20
ml) and stirred. A white solid remained, which could be suction
filtered (86 mg). The aqueous phase of the filtrate was extracted
with ethyl acetate (2.times.20 ml). The combined organic extracts
were dried and then concentrated by evaporation. The residue thus
obtained was identical to the solid obtained previously. Both
substances were combined. 219 mg of
N-(4-dimethylamino-4-pyridin-2-yl-cyclohexyl)-N-[2-(1H-indol-3-yl)-ethyl]-
-acetamide were obtained (m.p. 209.degree.-210.degree. C.), 195 mg
of which were dissolved in 2-butanone (25 ml) while gently warming
to 40.degree. C. and were converted into the corresponding
dihydrochloride with chlorotrimethyl-silane (0.303 ml) (white
solid; 219 mg; m.p. 244.degree.-247.degree. C.).
Example 106
[0527]
N'-[2-(1H-indol-3-yl)-ethyl]-N,N-dimethyl-1-pyridin-2-yl-cyclohexan-
e-1,4-diamine trihydrochloride, non-polar diastereomer
[0528] The
N'-[2-(1H-indol-3-yl)-ethyl]-N,N-dimethyl-1-pyridin-2-yl-cycloh-
exane-1,4-diamine (342 mg) obtained according to Example 105 was
dissolved in 2-butanone (20 ml) and converted into the
corresponding trihydrochloride (beige-coloured solid; 408 mg) with
chlorotrimethylsilane (0.59 ml).
Example 107
[0529]
N'-[2-(1H-indol-3-yl)-ethyl]-N,N-dimethyl-1-pyridin-2-yl-cyclohexan-
e-1,4-diamine trihydrochloride, polar diastereomer
[0530] As described for Example 105, 171 mg of the polar
diastereomer of
N'-[2-(1H-indol-3-yl)-ethyl]-N,N-dimethyl-1-pyridin-2-yl-cyclohexane-1,4--
diamine were also obtained, and were dissolved in 2-butanone (20
ml) and converted into the corresponding trihydrochloride with
chlorotrimethylsilane (0.297 ml) (171 mg of beige solid, m.p.
225.degree.-230.degree. C.).
Example 108
[0531]
N'-[2-(1H-indol-3-yl)-ethyl]-N,N-dimethyl-1-pyridin-2-yl-cyclohexan-
e-1,4-diamine trihydrochloride, non-polar diastereomer
[0532] The hydrochloride of L-tryptophan methyl ester (1.01 g) was
vigorously stirred for 15 minutes with 1,2-dichloroethane (20 ml)
and saturated NaHCO.sub.3 solution (20 ml) and the aqueous phase
was extracted with 1,2-dichloroethane (2.times.20 ml). After drying
over sodium sulfate the organic phase was concentrated by
evaporation to 40 ml and
4-dimethyl-amino-4-pyridin-2-yl-cyclohexanone (873 mg) was added
under argon. Glacial acetic acid (0.448 ml) and sodium sulfate (2
g) were added to the clear solution. After a reaction time of 15
minutes NaBH(OAc).sub.3 (1.2 g) was added to the reaction mixture
and stirred for 4 days at room temperature. For working-up
saturated NaHCO.sub.3 solution (40 ml) was added to the mixture and
stirred for 15 minutes. The aqueous phase was extracted with
dichloromethane (2.times.30 ml) and the combined organic phases
were dried and concentrated by evaporation, a pale brown oil being
obtained. Chromatographic separation of the substance mixture on
silica gel was carried out with ethyl acetate/methanol (4:1) and
methanol. The non-polar product (820 mg of slightly oily compound)
was dissolved in 2-butanone (50 ml) and converted with
chlorotrimethylsilane (1.22 ml) into the trihydrochloride (719 mg
of white hygroscopic solid; [.alpha.].sub.D.sup.20=19.85 (MeOH,
c=1.33)).
Example 109
[0533]
(S)-2-(4-dimethylamino-4-pyridin-2-yl-cyclohexylamino)-3-(1H-indol--
3-yl)-propionic acid methyl ester trihydrochloride, polar
diastereomer
[0534] As described for Example 108, 284 mg of the polar
diastereomer of
(S)-2-(4-dimethylamino-4-pyridin-2-yl-cyclohexylamino)-3-(1H-indol-3-yl)--
propionic acid methyl ester were also obtained, and were dissolved
in 2-butanone (15 ml) and converted into the corresponding
trihydrochloride with chlorotrimethylsilane (0.43 ml) (171 mg of
white solid, m.p. 170.degree.-175.degree. C.;
[.alpha.].sub.D.sup.20=17.61 (MeOH, c=1.45)).
Example 110
[0535]
(S)-2-(4-dimethylamino-4-pyridin-2-yl-cyclohexylamino)-3-(1H-indol--
3-yl)-propionic acid dihydrochloride, non-polar diastereomer
[0536] 1.7 N KOH (8.8 ml) was added to a solution of the non-polar
diastereomer of
N'-[2-(1H-indol-3-yl)-ethyl]-N,N-dimethyl-1-pyridin-2-yl--
cyclohexane-1,4-diamine trihydrochloride (378 mg) in ethanol (20
ml) prepared according to Example 108. After 70 hours the reaction
mixture was concentrated by evaporation, the remaining yellow oil
was dissolved in water (10 ml), the aqueous phase was washed with
ethyl acetate (3.times.20 ml), and 5.5 N HCl (9.0 ml) was added.
The aqueous phase was concentrated by evaporation and the residue
was digested with ethanol (2.times.20 ml). The remaining KCl was
separated and the filtrate was concentrated by evaporation and
washed with ether. The dihydrochloride of
(S)-2-(4-dimethylamino-4-pyridin-2-yl-cyclohexylamino)-3-(1H-indol-3-yl)--
propionic acid dihydrochloride (non-polar diastereomer) was thereby
obtained (307 mg; [.alpha.].sub.D.sup.20=20.69 (MeOH,
c=1.213)).
Example 111
[0537] .mu.-Binding
[0538] The affinity of the compounds for the .mu.-opioid receptor
was determined by known methods, in particular by a radioactive
displacement assay, and is expressed as Ki value in .mu.M.
1 TABLE 1 .mu.-Opioid Receptor Example K.sub.i (.mu.M) 94 0.0011 95
0.0012 96 0.0091 97 0.0021 98 0.079 99 0.014 100 0.0008 101 0.140
102 0.0210 103 91% (1 .mu.M)* 104 97% (1 .mu.M)* *91% (1 .mu.M)
denotes a displacement of about 91% at 1 .mu.M concentration
[0539] The investigated compounds all exhibited a pronounced
.mu.-binding, which clearly points to an analgesic action and
action according to the invention since the peripheral
.mu.-receptors are, as discussed in the introduction, involved in
irritable bowel disease as well as in diarrhea and also in
peripheeral analgesia and immunomodulation.
Example 112
[0540] Analgesia Testing in the Tail Flick Test in Mice
[0541] The mice were in each case placed individually in a test
cage and the base of the tail was exposed to the focussed radiant
heat from an electric lamp (tail flick type 50/08/1.bc, Labtec, Dr.
Hess). The lamp intensity was adjusted so that the time from
switching on the lamp up to the sudden withdrawal movement of the
tail (pain latency) was 3 to 5 seconds in untreated mice. Before
the i.v. administration of the solutions containing the compound
according to the invention or the respective comparison solutions,
the mice were pretested twice within 5 minutes and the mean value
of these measurements was calculated as a pre-test mean value.
[0542] The solutions of the compound of the general formula I as
well as the comparison solutions were then administered
intravenously. The pain measurement was carried out in each case
10, 20, 40 and 60 minutes after the intravenous administration. The
analgesic action was determined as the increase in the pain latency
(percent of the maximum possible antinociceptive effect according
to the following formula:
[(T.sub.1-T.sub.0)/(T.sub.2-T.sub.0)].times.100
[0543] Here the time T.sub.0 is the latency time before the
application, the time T.sub.1 is the latency time after the
application of the active substances combination, and the time
T.sub.2 is the maximum exposure time (12 seconds).
[0544] The ED.sub.50 was determined from several
concentration-dependent measurements. A more detailed investigation
of the analgesic effectiveness was carried out in the tail flick
test on mice, as described above.
[0545] The results of the selected investigations are summarised in
the following table.
2TABLE 2 Example No. CNS Analgesia 94 1.0-4.64 = ineff. 10.0 =
70-80% MPE 95 1.0-31.6 = ineff. 96 10.0 = ineff. 97 10.0-21.5 =
ineff. 98 10.0 = ineff. 99 10.0 = 48% MPE (5/10) 100 10.0 = ineff.
101 10.0 = ineff. 102 10.0 = ineff. 103 10.0 = ineff. Here the
figures refer to the employed concentrations in mg/kg i.v. ineff.
denotes ineffective up to this concentration in the tail flick test
in mice i.v. MPE denotes % maximum positive effect at this
concentration
[0546] The prepared investigated compounds showed despite a clear
.mu.-binding (see above; Example 111), which is clear evidence of
an analgesic effect according to the invention, no analgesic effect
in this model, which should be regarded as a pattern for the CNS
analgesic effect. If therefore these compounds bind strongly to the
.mu.-receptor but do not exhibit any CNS pain inhibition, this can
only mean that they bind to and act on the peripheral
.mu.-receptor--for example analgesically--and more specifically
without exhibiting CNS side effects.
Example 113
[0547] Diarrhea Suppression
[0548] Mice were investigated in the standard model of
PGE.sub.2-induced diarrhea. It was found that with an i.v.-applied
dose of 10 mg/kg (nearly) all animals exhibited a marked diarrhea
suppression:
3 TABLE 3 Example Diarrhea Suppression No. 10 mg/kg i.v. 94 10/10
95 10/10 96 9/10 97 10/10 98 10/10 99 10/10 100 10/10 101 10/10 102
10/10 103 10/10 10/10 denotes that 10 out of 10 animals at 10 mg/kg
exhibited a suppression of the diarrhea.
[0549] The ED.sub.50 value was determined from several
concentration-dependent measurements.
Example 114
[0550] Comparison of the Anti-diarrhea Action of Examples 94, 97,
96 and 98 with Loperamide:
[0551] The substance loperamide is a peripheral
opioid--acknowledged not to have any peripheral side effects--which
is used as an antidiarrhetic.
[0552] The ED.sub.50 values with i.v. administration in the known
model of PGE2-induced diarrhea are given as mg/kg.
4 TABLE 4 Example ED.sub.50 Value No. (mg/kg) i.v. Loperamide 0.41
95 0.23 94 0.53 97 0.78 96 2.77 98 3.88
Example 115
[0553] Comparison of the (Anti-diarrhea) Action of Example 95 with
Loperamide:
[0554] In direct comparison between Example 95 and loperamide the
following result was found:
5TABLE 5 Experiment Example 95 Loperamide Analgesia, tail flick
ineffective up ED.sub.50 > 0.562 test in mice, i.v. to 31.6
toxic from 0.464 According to Example 112 PGE.sub.2-diarrhea, mice
[.mu.M] ED.sub.50 i.v. = 0.23 ED.sub.50 i.v. = 0.41 ED.sub.50 p.o.
= 12.6 ED.sub.50 p.o. = 9.34 Carbon passage, mice ED.sub.50 i.v. =
0.32 ED.sub.50 i.v. = n.m. [.mu.M] ED.sub.50 p.o. = n.m. ED.sub.50
p.o. = .about.15 n.m. denotes not measured. Toxic denotes toxic
side effects
[0555] The PGE.sub.2 diarrhea test as well as the carbon passage
are known standard test systems for diarrhea. The ED.sub.50 was
determined from several concentration-dependent measurements.
Administration was performed both i.v. as well as p.o.
[0556] Example 95 shows many advantages compared to loperamide. On
the one hand Example 95 is completely ineffective on the central
nervous system, in contrast to loperamide, which always has a
measurable action on the central nervous system; this means that
significantly fewer side effects can be expected with Example 95
than with loperamide. Example 95 turns out to be just as good or
better than loperamide in the PGE.sub.2 diarrhea test, which is
also confirmed by the carbon passage measurement.
Example 116
[0557] Parenteral Solution of a Substituted cyclohexane-1,4-diamine
Compound
[0558] 38 g of one of the substituted cyclohexane-1,4-diamine
compounds according to the invention, here according to Example 95,
is dissolved in 1 l of water for injection purposes at room
temperature and is then adjusted to isotonic conditions by addition
of anhydrous glucose for injection purposes.
[0559] 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.
* * * * *